Preparation of multisubstituted enamides via rhodium-catalyzed carbozincation and hydrozincation of ynamides

Article abstract of DOI:10.1021/jo901658v

(Chemical Equation Presented) Rhodium-catalyzed carbozincation of ynamides using diorganozinc reagents or functionalized organozinc halides is described.Using a tri(2-furyl)phosphine-modified rhodium catalyst, the reaction course is altered to hydrozincation when diethylzinc is employed as the organozinc reagent. Trapping of the alkenylzinc intermediates produced in these reactions in further functionalization reactions is possible. Collectively, these processes enable access to a range of multisubstituted enamides in stereo- and regiocontrolled fashion.

Full text of DOI:10.1021/jo901658v

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Preparation of Multisubstituted Enamides via Rhodium-Catalyzed
Carbozincation and Hydrozincation of Ynamides
Benoit Gourdet, Mairi E. Rudkin, Ciorsdaidh A. Watts, and Hon Wai Lam*
School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings,
West Mains Road, Edinburgh, EH9 3JJ, United Kingdom
h.lam@ed.ac.uk
Received July 30, 2009
Rhodium-catalyzed carbozincation of ynamides using diorganozinc reagents or functionalized organozinc
halides is described. Using a tri(2-furyl)phosphine-modified rhodium catalyst, the reaction course is altered
to hydrozincation when diethylzinc is employed as the organozinc reagent. Trapping of the alkenylzinc
intermediates produced in these reactions in further functionalization reactions is possible. Collectively,
these processes enable access to a range of multisubstituted enamides in stereo- and regiocontrolled fashion.
Introduction
hydrogenation2 and a variety of other useful transforma-
tions.1,3 In addition, the enamide moiety appears in several
biologically active natural products such as TMC-95A-D,4
crocacins A, B, and D,5 and the salicylihalamides and related
compounds.6 Accordingly, the stereo- and regiocontrolled
synthesis of enamides is an important endeavor.
Among the various strategies available to access enamides,
one important class of reactions involves carbon-nitrogen
bond formation on the corresponding amide, carbamate, or
sulfonamide. In this context, a traditional and widely adopted
approach is condensation with a carbonyl compound.7 How-
ever, application of this method to the synthesis of more highly
substituted enamides is often plagued with problems of regio-
control and/or E/Z stereocontrol during the dehydration step,
In recent years, enamides1 have gained increasing atten-
tion as valuable synthetic intermediates for asymmetric
(1) For reviews on enamides, see: (a) Carbery, D. R. Org. Biomol. Chem.
2008, 6, 3455–3460. (b) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008,
41, 292–301. (c) Larock, R. C. Comprehensive Organic Transformations: A
Guide to Functional Group Preparations; Wiley-VCH: New York, 1999.
(d) Tracey, M. R.; Hsung, R. P.; Antoline, J.; Kurtz, K. C. M.; Shen, L.; Slafer,
B. W.; Zhang, Y. In Science of Synthesis, Houben-Weyl Methods of Molecular
Transformations; Weinreb, S. M., Ed.; Georg Thieme Verlag KG: New York
1999; Chapter 21.4.
(2) (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–3070. (b) Blaser,
H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth.
Catal. 2003, 345, 103–151. (c) Brown, J. M. Mechanism of enantioselective
hydrogenation. Handbook of Homogeneous Hydrogenation; De Vries, J. G.,
Elsevier, C. J., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
Germany, 2007. (d) Jaekel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912–2942.
(e) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278–1290.
(3) For recent, selected reactions of enamides, see: (a) Satyanarayana, G.;
(4) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.;
Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990–995.
€
Maichle-Mossmer, C.; Maier, M. E. Chem. Commun. 2009, 1571–1573.
€
(b) Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 1075–1078. (c) Friestad,
G. K.; Wu, Y. Org. Lett. 2009, 11, 819–822. (d) Baudequin, C.; Zamfir, A.;
Tsogoeva, S. B. Chem. Commun. 2008, 4637–4639. (e) Aciro, C.; Davies,
S. G.; Garner, A. C.; Ishii, Y.; Key, M.-S.; Ling, K. B.; Prasad, R. S.;
Roberts, P. M.; Rodriguez-Solla, H.; O’Leary-Steele, C.; Russell, A. J.;
Sanganee, H. J.; Savory, E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron
2008, 64, 9320–9344. (f) Lu, T.; Song, Z.; Hsung, R. P. Org. Lett. 2008, 10,
541–544. (g) Berthiol, F.; Matsubara, R.; Kawai, N.; Kobayashi, S. Angew.
Chem., Int. Ed. 2007, 46, 7803–7805. (h) Song, Z.; Lu, T.; Hsung, R. P.;
Al-Rashid, Z. F.; Ko, C.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 4069–
4072. (i) Gohier, F.; Bouhadjera, K.; Faye, D.; Gaulon, C.; Maisonneuve, V.;
Dujardin, G.; Dhal, R. Org. Lett. 2007, 9, 211–214. (j) Ko, C.; Hsung, R. P.;
Al-Rashid, Z. F.; Feltenberger, J. B.; Lu, T.; Yang, J.-H.; Wei, Y.; Zificsak,
C. A. Org. Lett. 2007, 9, 4459–4462. (k) Barbazanges, M.; Meyer, C.; Cossy,
J. Org. Lett. 2007, 9, 3245–3248.
(5) (a) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot.
1994, 47, 881-886. (b) Jansen, R.; Washausen, P.; Kunze, B.; Reichenbach,
H.; Hofle, G. Eur. J. Org. Chem. 1999, 1085-1089.
(6) Yet, L. Chem. Rev. 2003, 103, 4283–4306.
(7) For an early reference, see: Zezza, C. A.; Smith, M. B. Synth.
Commun. 1987, 17, 729–740.
(8) For examples of enamide synthesis relying upon palladium-catalyzed
C-N bond formation, see: (a) Kozawa, Y.; Mori, M. J. Org. Chem. 2003, 68,
3064–3067. (b) Brice, J. L.; Meerdink, J. E.; Stahl, S. S. Org. Lett. 2004, 6,
1845–1848. (c) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.; Volante, R. P. Org.
Lett. 2003, 5, 4749–4752. (d) Klapars, A.; Campos, K. R.; Chen, C.-y.;
Volante, R. P. Org. Lett. 2005, 7, 1185–1188. (e) Lee, J. M.; Ahn, D.-S.; Jung,
D. Y.; Lee, J.; Do, Y.; Kim, S. K.; Chang, S. J. Am. Chem. Soc. 2006, 128,
€
ꢀ
12954–12962. (f) Barluenga, J.; Moriel, P.; Aznar, F.; Valdes, C. Org. Lett.
2007, 9, 275–278.
DOI: 10.1021/jo901658v
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J. Org. Chem. 2009, 74, 7849–7858 7849
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Gourdet et al.
JOCArticle
resulting in an unwieldy mixture of isomers. With advances in
cross-coupling technology, another attractive method to prepare
enamides from their parent N-H compounds is via palladium-8
or copper-catalyzed9 N-alkenylation reactions.10 By using this
approach, however, the problems of regio- and stereocontrol are
now transferred to the synthesis of the alkenyl coupling partners.
A further means to access enamides involving C-N bond
formation is the catalytic hydroamidation of terminal alkynes.11
Although both E-andZ-enamides may be prepared selectively,11
this method is currently limited to the preparation of β-mono-
substituted products.
A second major strategy for enamide preparation involves
the use of ynamide12 starting materials, since developments
in alkynyliodonium salt chemistry13 along with copper-14
and iron-catalyzed15 alkynylation methodology have meant
that a variety of ynamides are now readily available. Repre-
sentative intermolecular examples of this approach include
hydroboration of ynamides followed by Suzuki-Miyaura
coupling16a or homologation,16b hydro- or silylstannylation
of ynamides followed by Stille coupling17a,b or lithiation-
electrophilic trapping,17c hydrohalogenation of ynamides
followed by Sonogashira coupling,18 and various reductive
coupling reactions.19 Relevant intramolecular examples in-
clude domino Heck-Suzuki-Miyaura reactions,20 keteni-
minium cyclizations,21 ring-closing enyne metathesis,22 and
platinum-catalyzed cycloisomerizations.23 While these reac-
tions generally work quite well, they are often restricted to
the production of only certain classes of products, or require
rather specialized substrates.
Although enamides may also be prepared using a number
of other methods,24 we recently became interested in the
carbometalation25 of ynamides as a general route to multi-
substituted enamides. As the majority of carbometalation
reactions occur in a syn-fashion,25 issues of selectivity during
ynamide carbometalation are reduced to one of regioselec-
tivity, provided isomerization does not occur. In addition,
utilization of the alkenylmetal intermediates that are pre-
sumably generated during ynamide carbometalation in
further functionalization reactions should allow the prepara-
tion of more highly substituted products. At least in principle
therefore, ynamide carbometalation should represent one of
the simplest and most flexible approaches to multisubsti-
tuted enamides.
In a seminal study, Marek and co-workers described
intermolecular carbocupration and copper-catalyzed carbo-
magnesiation of two ynamides,26 and this methodology has
been employed by others during a study of aza-Claisen
rearrangements.27 More recently, the ynamide carbocupra-
tion variant was exploited in an interesting approach to
access aldol products containing all-carbon quaternary
stereocenters.28 Despite these developments, there remains
scope for improvement. For example, in the more attractive
copper-catalyzed carbomagnesiation variant, the presence of
base- and nucleophile-sensitive functional groups on the
ynamide is restricted due to the excess Grignard reagent in
solution. Furthermore, the prospects of sensitive functional
(9) For examples of enamide synthesis relying upon copper-catalyzed
C-N bond formation, see: (a) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H.
Chem. Lett. 1991, 1443–1446. (b) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000,
2, 1333–1336. (c) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org.
Lett. 2003, 5, 3667–3669. (d) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr. Org.
Lett. 2004, 6, 27–30. (e) Coleman, R. S.; Liu, P.-H. Org. Lett. 2004, 6, 577–
580. (f) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809–1812. (g) Shen, L.;
Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett. 2005, 7, 3081–
3084. (h) Hu, T.; Li, C. Org. Lett. 2005, 7, 2035–2038. (i) Sun, C.; Camp, J. E.;
Weinreb, S. M. Org. Lett. 2006, 8, 1779–1781. (j) Yang, L.; Deng, G.; Wang,
D.-X.; Huang, Z.-T.; Zhu, J.-P.; Wang, M.-X. Org. Lett. 2007, 9, 1387–1390.
(k) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett.
2003, 44, 4927–4931. (l) Bolshan, Y.; Batey, R. A. Angew. Chem., Int. Ed.
2008, 47, 2109–2112.
(10) For relevant reviews, see: (a) Dehli, J. R.; Legros, J.; Bolm, C. Chem.
Commun. 2005, 973–986. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem.
Rev. 2008, 108, 3054–3131.
(11) (a) Kondo, T.; Tanaka, A.; Kotachi, S.; Watanabe, Y. J. Chem. Soc.,
Chem. Commun. 1995, 413–414. (b) Goossen, L. J.; Rauhaus, J. E.; Deng, G.
Angew. Chem., Int. Ed. 2005, 44, 4042–4045. (c) Goossen, L. J.; Blanchot, M.;
Brinkmann, C.; Goossen, K.; Karch, R.; Rivas-Nass, A. J. Org. Chem. 2006,
71, 9506–9509. (d) Yudha, S.; Kuninobu, Y.; Takai, K. Org. Lett. 2007, 9,
5609–5611. (e) Goossen, L. J.; Salih, K. S. M.; Blanchot, M. Angew. Chem.,
Int. Ed. 2008, 47, 8492–8495. (f) Goossen, L. J.; Arndt, M.; Blanchot, M.;
Rudolphi, F.; Menges, F.; Niedner-Schatteburg, G. Adv. Synth. Catal. 2008,
350, 2701–2707.
(18) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.;
Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547–1550.
(19) (a) Saito, N.; Katayama, T.; Sato, Y. Org. Lett. 2008, 10, 3829–3832.
(b) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67–70.
(c) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727–729.
(20) Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Tetrahedron 2006, 62,
3882–3895.
(12) For general reviews of ynamide chemistry, see: (a) Zificsak, C. A.;
Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001,
57, 7575–7606. (b) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003,
1379–1390. (c) Katritzky, A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63,
1455–1475.
(13) For example, see: (a) Feldman, K. S.; Bruendl, M. M.; Schildknegt,
K.; Bohnstedt, A. C. J. Org. Chem. 1996, 61, 5440–5452. (b) Witulski, B.;
Stengel, T. Angew. Chem., Int. Ed. 1998, 37, 489–492. (c) Witulski, B.;
(21) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis,
A. Org. Lett. 2005, 7, 1047–1050.
(22) (a) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder,
J. A.; Grebe, T. P. Org. Lett. 2002, 4, 2417–2420. (b) Saito, N.; Sato, Y.;
Mori, M. Org. Lett. 2002, 4, 803–805. (c) Mori, M.; Wakamatsu, H.; Saito,
N.; Sato, Y.; Narita, R.; Sato, Y.; Fujita, R. Tetrahedron 2006, 62, 3872–
3881.
(23) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria,
M. Org. Lett. 2004, 6, 1509–1511.
€
Gossmann, M. Chem. Commun. 1999, 1879–1880. (d) Tanaka, K.; Takeishi,
K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586–4587.
(24) For example, see the following and references cited therein: (a) Guan,
Z.-H.; Huang, K.; Yu, S.; Zhang, X. Org. Lett. 2009, 11, 481–483. (b) Savarin,
C. G.; Boice, G. N.; Murry, J. A.; Corley, E.; DiMichele, L.; Hughes, D. Org.
Lett. 2006, 8, 3903–3906. (c) van den Berg, M.; Haak, R. M.; Minnaard, A. J.;
de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Adv. Synth. Catal. 2002, 344,
1003–1007. (d) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63,
6084–6085. (e) Sato, M. J. Org. Chem. 1961, 26, 770–779.
(25) For general reviews on carbometalation reactions, see: (a) Marek, I.;
Chinkov, N.; Banon-Tenne, D. In Metal-Catalyzed Cross-Coupling Reactions;
de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
pp 395-478. (b) Marek, I.; Normant, J. F. In Transition Metals for Organic
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH, Weinheim, Germany, 1998;
pp 514-522.
(26) Chechik-Lankin, H.; Livshin, S.; Marek, I. Synlett 2005, 2098–2010.
(27) (a) Yasui, H.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2007, 36, 32–
33. (b) Yasui, H.; Yorimitsu, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2008, 81,
373–379.
(28) Prakash Das, J.; Chechik, H.; Marek, I. Nature Chem. 2009, 1, 128–
132.
(14) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003,
125, 2368–2369. (b) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011–
4014. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L.
Org. Lett. 2004, 6, 1151–1154. (d) Riddell, N.; Villeneuve, K.; Tam, W. Org.
Lett. 2005, 7, 3681–3684. (e) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.;
Kurtz, K. C. M.; Oppenheimer, J.; Peterson, M. E.; Sagamanova, I. K.; Shen,
L.; Tracey, M. R. J. Org. Chem. 2006, 71, 4170–4177. (f) Hamada, T.; Ye, X.;
Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–835. (g) Coste, A.; Karthikeyan,
G.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2009, 48, 4381–4385.
(15) Yao, B.; Liang, Z.; Niu, T.; Zhang, Y. J. Org. Chem. 2009, 74, 4630–
4633.
€
(16) (a) Witulski, B.; Buschmann, N.; Bergstrasser, U. Tetrahedron 2000,
56, 8473–8480. (b) Hoffmann, R. W.; Bruckner, D. New J. Chem. 2001, 25,
€
369–373.
(17) (a) Timbart, L.; Cintrat, J. C. Chem.;Eur. J. 2002, 8, 1637–1640.
(b) Buissonneaud, D.; Cintrat, J.-C. Tetrahedron Lett. 2006, 47, 3139–3143.
(c) Naud, S.; Cintrat, J.-C. Synthesis 2003, 1391–1397.
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TABLE 1. Optimization of Carbometalation Reaction Conditions
FIGURE 1. Ynamides initially examined in this study.
entry
precatalyst
EtnM
Et3Al complex mixture
Et3B no reaction
Et3Al no reaction
Et2Zn 2:3:4 formed in 8:1:2 ratioa
Rh(cod)(acac) Et3B no reaction
result
1
2
3
4
5
6
7
Fe(acac)3
Ni(acac)2
groups residing on the organometallic reagent itself are
somewhat limited with Grignard reagents.29 Therefore, the
development of complementary ynamide carbometalation
procedures using more functional group-tolerant organome-
tallics is desirable. Recently, we described highly stereo- and
regiocontrolled rhodium-catalyzed carbozincations of yna-
mides that enable efficient access to a range of multisubsti-
tuted enamides.30 In this article, a more detailed account of
this work is provided, including further demonstration of the
utility of our catalytic system, the compatibility of the
protocol with a greater range of functionalized organozinc
halide reagents, the effect of exogenous ligands on the course
of the reaction, and the reactivity of the alkenylzinc inter-
mediates in further transformations with various electro-
philes. Investigations into the synthetic utility of the resulting
enamides and dienamides are also described.
Et3Al no reaction
Et2Zn 2:3 formed in 14:1 ratio after 15 min;a
73% isolated yield of 2
8
CuI
Et2Zn 2:3 formed in >19:1 ratio after 20 h;a
65% isolated yield of 2.
9
;
Et2Zn ca. 3-4% of 2 formed after 18 h
aReactions proceeded to complete conversion. Ratios determined by
1H NMR analysis of the unpurified reaction mixtures.
With efficient conditions in hand (Table 1, entry 7), the
scope and limitation of this process was explored by using
commercially available dialkylzinc reagents (Table 2). A
variety of ynamides containing oxazolidin-2-one, pyrroli-
din-2-one, or cyclic urea functionality smoothly under-
went carbometalation with acceptable to excellent regio-
selectivities and generally good yields. Alkyl (entries 1-8
and 12) and aryl (entries 9-11, 13, and 14) substituents
on the ynamide were tolerated, and in addition to Et2Zn,
both Me2Zn and n-Bu2Zn were effective dialkylzinc re-
agents for these reactions. In some cases, lower regioselec-
tivities were observed with Me2Zn (entries 1, 7, and 9).
Ynamide 1g containing a chiral oxazolidin-2-one was also
a competent substrate, reacting smoothly with Et2Zn to
provide chiral enamide 15 (entry 12). This example bodes
well for the synthesis of chiral enamides that could
prove useful in a range of asymmetric reactions.3e,f,h-j
The reaction is also successful with smaller quantities
of the precatalyst and the dialkylzinc reagent, as demon-
strated by carbometalation of 1f with 2 mol % of Rh(cod)-
(acac) and 0.55 equiv of Et2Zn, which provided 13 in
69% yield (entry 10). This result also shows that transfer
of both alkyl groups from zinc is possible. In a few cases,
small quantities of reduced products (R2 = H) resulting
from ynamide hydrometalation were detected in the un-
purified reaction mixtures (entries 11 and 13), and a more
detailed discussion of this phenomenon is provided later
(vide infra).
Results and Discussion
The ynamides that were initially employed in this study are
shown in Figure 1, and were prepared by copper-catalyzed
N-alkynylation reactions of the parent N-H compound
according to literature protocols.14c,e,f Using ynamide 1a as
a test substrate, our studies commenced with a survey of
various combinations of organometallic reagents and metal
salts with the goal of identifying effective conditions for
carbometalation (Table 1). Conditions that were effective for
carbometalation of bis-activated cyclopropenes31 were un-
successful with ynamide 1a (entry 1). Using Ni(acac)2 as a
precatalyst, no reaction was observed with trialkylborane or
trialkylaluminum reagents (entries 2 and 3), but diethylzinc
was found to provide a mixture of regioisomeric addition
products 2 and 3, along with the reduction product 4, in high
conversion (entry 4).32 Switching the precatalyst to Rh(cod)-
(acac), the use of Et3B and Et3Al gave no reaction (entries 5
and 6). However, Et2Zn furnished enamide 2 with high
regioselectivity (14:1) in 73% isolated yield in only 15 min
(entry 7), with no trace of 4. Although CuI was also an
effective precatalyst, the reaction time was greatly increased
to 20 h and the isolated yield of 2 was only 65% (entry 8).
A control experiment performed with Et2Zn in the absence
of any precatalyst provided ca. 3-4% of 2 after 18 h,
demonstrating that a slow uncatalyzed background reaction
is operative (entry 9).
Restriction of this process to the limited range of commer-
cially available diorganozinc reagents would place a serious
constraint on the generality of this methodology. Therefore,
studies were undertaken to develop a method employing
other readily available organometallics. Although this study
was motivated by the desire to use organometallics that
exhibit broad functional group tolerance, the ready avail-
ability of Grignard reagents prompted us to examine them
using Rh(cod)(acac) as the precatalyst. Unfortunately, these
reactions were unsuccessful, providing complex mixtures of
unidentified products. Pleasingly, we discovered that the
(29) For a review of polyfunctionalized organometallics, including
Grignard reagents, see: Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P.
Angew. Chem., Int. Ed. 2000, 39, 4414–4435.
(30) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 3802–3803.
(31) Wang, Y.; Fordyce, E. A. F.; Chen, F. Y.; Lam, H. W. Angew.
Chem., Int. Ed. 2008, 47, 7350–7353.
€
(32) Fornickel-catalyzedcarbozincationof arylalkynes, see: (a) Studemann,
T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1997, 36, 93–95. (b) Studemann, T.;
Ibrahim-Ouali, M.; Knochel, P. Tetrahedron 1998, 54, 1299–1316.
€
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JOCArticle
TABLE 2. Rh-Catalyzed Carbozincation of Ynamides
TABLE 3. Carbozincation Using in Situ-Generated Diorganozincs
arr=Regioisomeric ratio as determined by 1H NMR analysis of the
unpurified reaction mixtures. bIsolated yield of major regioisomer.
cYield of a 14:1 mixture of regioisomers. dYield in parentheses refers
to reaction with 2 mol % of Rh(cod)(acac) and 0.55 equiv of Et2Zn,
e
which took 4 h to complete. Ca. 5% of the hydrometalation product
(R2 =H) was detected in the unpurified reaction mixture.
corresponding diorganozinc reagents generated in situ by
transmetalation of the Grignard reagent with ZnCl2 were
much more effective (Table 3). For example, reaction of
ynamide 1j with dibenzylzinc (1.0 equiv) generated from
BnMgCl (2.0 equiv) and ZnCl2 (1.0 equiv) provided enamide
18 as the only observable regioisomer in 71% yield (entry 1).
In similar fashion, carbometalation with para-substituted
aromatic (entries 2 and 3) and 2-thienyl (entry 4) groups was
possible, and dienamides may be accessed by carbometala-
tion with vinyl (entries 5 and 6) and 2-propenyl (entry 7)
groups. In certain cases, acceptable regioselectivities were
obtained only by decreasing the reaction temperature to -78 °C
(entries 4-6). The use of dicyclopropylzinc proved to be more
challenging, and reaction with ynamide 1i provided regioiso-
meric products 25a and 25b in 47% and 30% yield, respectively,
even with an initial reaction temperature of -78 °C (entry 8).
Transfer of an alkynyl substituent was also possible, but requi-
red a higher precatalyst loading (40%) for reasonable yields
(entry 9).
arr = Regioisomeric ratio as determined by 1H NMR analysis of the
unpurified reaction mixtures. bIsolated yield of regioisomerically pure
material. cReaction conducted with BnMgCl. dReaction conducted at an
initial temperature of -78 °C. Reaction conducted with 40 mol % of
Rh(cod)(acac).
e
functionalized diorganozincs may be prepared by using
other procedures,33 expansion of the organometallic reagent
scope to encompass organozinc halides would be attractive,
since a number of these reagents (including functionalized
derivatives) are now commercially available, and insertion of
While straightforward, the reliance on Grignard reagents
as the source of the diorganozinc species in the reactions
in Table 3 limits the presence of base- and nucleophile-
sensitive functional groups in the organometallic. Although
(33) (a) Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57,
1956–1958. (b) Vettel, S.; Vaupel, A.; Knochel, P. J. Org. Chem. 1996, 61,
7473–7481. (c) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.;
Knochel, P. J. Org. Chem. 1996, 61, 8229–8243. (d) Charette, A. B.;
Beauchemin, A.; Marcoux, J.-F. J. Am. Chem. Soc. 1998, 120, 5114–5115.
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TABLE 4. Carbozincation Using Organozinc Halides
SCHEME 1. Carbometalation of Ynamide 1i with Alkylzinc
Bromide 27c
27d the regioselectivity was diminished, and the yield was
lowered by a competing hydrometalation pathway (entry 7).
For reasons that are unclear at this time, the benzylzinc
reagent 27e displayed sluggish reactivity, and required the
use of modified conditions (5 mol % of [Rh(cod)Cl]2 with
10 mol % of rac-BINAP at 60 °C) to deliver the product
35 in 35% yield along with other unidentified products
(entry 8).
Reaction of aliphatic zinc bromide 27c with ynamide 1i
was particularly problematic under our original condi-
tions, and provided a complex mixture of products from
which carbometalation and hydrometalation products 36
and 37 were isolated in 25% and 15% yield, respectively
(Scheme 1). The remaining mass balance appeared to be
composed of the regio- and/or stereoisomer of 36, along
with other unidentified products. In this case, replace-
ment of Rh(cod)(acac) with Cu(acac)2 (10 mol %) elimi-
nated the formation of the hydrometalation product 37
and increased the regioselectivity, allowing 36 to be iso-
lated in improved yield.35 However, Cu(acac)2 was com-
pletely ineffective in conjunction with arylzinc halide
reagents, and only starting materials were recovered in
these reactions.
All of the ynamides examined until this point have the
carbonyl group embedded within a five-membered ring, such
as an oxazolidin-2-one, pyrrolidin-2-one, or a cyclic urea. It
was therefore of interest to evaluate rhodium-catalyzed carbo-
zincations of acyclic ynamides, and representative examples of
substrates studied are shown in Figure 2.
arr = Regioisomeric ratio as determined by 1H NMR analysis of the
unpurified reaction mixtures. bIsolated yield of major regioisomer. cThe
hydrometalation product 4 was also isolated in 12% yield. dThe ratio of
isomers could not be determined due to the complexity of the unpurified
reaction mixture. eResult obtained with [Rh(cod)Cl]2 (5 mol %) and rac-
BINAP (10 mol %) at 60 °C for 6 h.
FIGURE 2. Acyclic ynamides examined in this study.
Under standard conditions with Et2Zn as the organozinc
reagent, it quickly became evident that acyclic ynamides
provided unsatisfactory results. For example, ynamides
containing an aliphatic substituent on the triple bond such
as 38a failed to undergo carbozincation, the only result being
a small degree of substrate decomposition. Phenyl-substi-
tuted acyclic ynamides were much more reactive, and carbo-
zincation of the Boc-protected substrate 38b proceeded
zinc into polyfunctional iodides may be used to access a
wider range of derivatives.29,34
Fortunately, the addition of organozinc halides was suc-
cessful under our original conditions (Table 4). A variety of
organozinc halide reagents were well-tolerated in the reac-
tion; arylzinc iodides containing an ester (entries 1-3) or a
chlorine (entries 4 and 5) gave the carbometalation products
in generally good yields and high regioselectivities. The use of
aliphatic zinc bromide reagents was also successful (entries 6
and 7), though in the case of the nitrile-substituted reagent
(35) For examples of copper-catalyzed addition of organozinc halides to
alkynes, see: (a) Maezaki, N.; Sawamoto, H.; Yoshigami, R.; Suzuki, T.;
Tanaka, T. Org. Lett. 2003, 5, 1345–1347. (b) Maezaki, N.; Sawamoto, H.;
Suzuki, T.; Yoshigami, R.; Tanaka, T. J. Org. Chem. 2004, 69, 8387–8393.
(c) Sklute, G.; Bolm, C.; Marek, I. Org. Lett. 2007, 9, 1259–1261.
(34) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117–2188.
J. Org. Chem. Vol. 74, No. 20, 2009 7853

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rapidly even at low temperatures (eq 1). Unfortunately, the
selectivity of this reaction was poor, marginally favoring the
unexpected regioisomer 39b. Attempts to improve the re-
gioselectivity through screening of ligands and solvent were
unsuccessful. Although N-tosyl ynamide 38c was also reac-
tive toward rhodium-catalyzed carbozincation with Et2Zn
(products were not isolated), once again minimal regioselec-
tivity (ca. 1:1.4) was observed.
TABLE 5. Investigation of Ligand Effectsa
entry
Rh salt
ligand
4:2b
1
2
3
4
5
6
7
8
9
[Rh(cod)Cl]2
Rh(cod)(MeCN)2BF4
RhCl(PPh3)3
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
;
;
;
Ph3P
Bu3P
<1:19
<1:19
5:1
9:1c
<1:19
<1:19
>19:1c
(rac)-BINAP
(p-F-Ph)3F
(2-Thienyl)3P
(2-Fur)3P
>19:1c
12:1
aAll reactions proceeded to complete conversion. Carbometalation
product 2 was generally obtained in g19:1 regioisomeric ratio. bRatios
determined by 1H NMR analysis of the unpurified reaction mixtures.
cHydrometalation product 4 had a stereoisomeric composition of ca.
10:1 Z:E.
In view of the improvements observed upon replacement
of Rh(cod)(acac) with Cu(acac)2 in the carbozincation of
ynamide 1i with alkylzinc bromide 27c (Scheme 1), Cu(acac)2
was also examined in the carbometalation of acyclic sub-
strates 38a-38c with Et2Zn. Although 38a and 38c were
largely inert to these conditions, improved results were
observed with Boc-protected substrate 38b with Et2O as
solvent, albeit in a much slower reaction, with enamide 39a
isolated in 66% yield and with >19:1 rr after 16 h (eq 2).
Attempted carbozincations of acyclic ynamides with alkyl-
zinc halides by using either Rh(cod)(acac) or Cu(acac)2 did
not provide satisfactory results, furnishing complex mixtures
of products, and in the case of the copper-catalyzed proce-
dure, low conversions were observed. Reactions of acyclic
ynamides with arylzinc halides gave mostly unchanged start-
ing materials.
We assume that the high reactivities and regioselectivities
observed in the carbozincation of ynamides containing cyclic
carbamate, amide, or urea groups are in part due to an
efficient directing group effect36 from the carbonyl function
in coordinating to the rhodium and/or zinc centers in the
carbometalation step (vide infra). Therefore, the unsatisfac-
tory results obtained with acyclic ynamides may be a result of
the greater rotational freedom of these substrates, which
might be translated into diminished directing group ability of
the carbonyl/sulfonyl groups. In this context, the carbocu-
pration and copper-catalyzed carbomagnesiation reactions
first described by Marek and co-workers26-28 remain the
methods of choice for carbometalation of acyclic ynamides.
During the course of these studies, hydrometalation was
observed as a competing process in several cases (Table 2,
entries 11 and 13; Table 4, entry 7; and Scheme 1). Presum-
ably, this pathway occurs as a result of β-hydride elimination
taking place when the organometallic reagent contains a
β-hydrogen-containing alkyl group. Although the resulting
β-monosubstituted Z-enamides are best obtained by Lindlar
reduction of the corresponding ynamides,14e,37 it was never-
theless of interest to study this hydrometalation pathway in
more depth. As well as possibly providing further informa-
tion about this catalyst system that could guide future
developments, it was hoped the hydrometalation pathway
could enable access to enamides of a substitution pat-
tern complementary to that obtained from carbometalation
(vide infra).
Accordingly, modification of the catalyst through vari-
ation of the rhodium source and addition of exogenous
ligands was undertaken in the reaction of ynamide 1a with
Et2Zn, with the expectation that alteration of the steric/
electronic properties of the rhodium center through coun-
terion and ligand effects could render the hydrometalation
process more favorable (Table 5). Although switching the
precatalyst from Rh(cod)(acac) to [Rh(cod)Cl]2 or Rh-
(cod)(MeCN)2BF4 had minimal effect (entries 1 and 2,
respectively, compare with Table 1, entry 7), Wilkinson’s
catalyst38 provided a 5:1 mixture of the hydrometalation
product 4 and the carbometalation product 2, respectively
(entry 3). Triphenylphosphine-modified [Rh(cod)Cl]2 in-
creased the selectivity in favor of hydrometalation further,
though a small quantity of the E-isomer of 4 was also
observed (entry 4). Use of a stronger σ-donor ligand
(Bu3P, entry 5) or a bidentate ligand (rac-BINAP, entry
6) switched the selectivity back in favor of carbometala-
tion. Good π-acceptor phosphines afforded the best selec-
tivities (g12:1 in favor of hydrometalation, entries 7-9),
though appreciable quantities of the E-isomer of 4
were also produced by using (p-F-Ph)3P or (2-Thienyl)3P
(entries 7 and 8, respectively). The cleanest conversion to
hydrometalation product 4 occurred with (2-Fur)3P (entry 9).
In all cases, reactions using phosphine-modified catalysts
proceeded at a significantly decreased rate compared with
those using phosphine-free precatalysts, regardless of
whether hydrometalation or carbometalation was the
dominant pathway (up to 6 h for complete conversion,
compare with results in Table 2 which required only
15 min). Therefore, it is possible that the slow uncatalyzed
background reaction (Table 1, entry 9) is responsible for
small quantities of 2 observed in some of these hydro-
metalation reactions.
(36) For a review of substrate-directable chemical reactions, see: Hoveyda,
A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307–1370.
(37) Other types of Z-enamides may be accessed efficiently through
catalytic hydroamidation of terminal alkynes. See refs 11c and 11e.
(38) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Chem.
Soc. A 1966, 1711–1732.
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TABLE 6. Hydrometalation of Ynamides
SCHEME 2. Possible Catalytic Cycle for Ynamide Carbo-
metalation
SCHEME 3. Possible Catalytic Cycle for Ynamide Hydro-
metalation
aSelectivity=ratio of hydrometalation (R2=H) to carbometalation
(R2=Et) as determined by 1H NMR analysis of the unpurified reaction
mixtures. bUnless otherwise stated, isolated yield of an inseparable
mixture of hydrometalation and carbometalation product in a ratio
identical with that measured from the unpurified reaction mixtures.
cIsolated yield of a 9:1 mixture of hydrometalation product 4 and
carbometalation product 2. dIsolated yield of pure hydrometalation
product. eThe E-hydrometalation productwas also detected (proportion
in parentheses). fThe complex mixture was not purified.
species 48 that is protonated upon workup. However, this
mechanism may be an oversimplified representation, and
involvement of an organozinc species in the carbometala-
tion event through interactions with the ynamide carbonyl
group and/or the rhodium center seems possible. Further
investigations will be required to shed light on the finer
details of the mechanism.
In the complementary hydrometalation procedure with
[Rh(cod)Cl]2 and (2-Fur)3P, we assume that when a β-hy-
drogen is present in the organorhodium species 49, the
altered electronic properties of the phosphine-ligated
rhodium center leads to β-hydride elimination occurring
partially at the expense of ynamide carbometalation
(Scheme 3). The resulting rhodium hydride 50 then parti-
cipates in a carbonyl-directed syn-hydrometalation of the
ynamide 1 to provide alkenylrhodium species 51 that
undergoes transmetalation with an organozinc species to
give alkenylzinc species 52, liberating 49 to reenter the
catalytic cycle.
Both of these mechanisms suggested that more highly
substituted enamides might be accessed through utilization
of the alkenylzinc species 48 and 52 in further functionaliza-
tion reactions. This strategy was first explored within the
context of ynamide carbometalation. Carbozincation of
ynamide 1f with 0.55 equiv of Et2Zn provided alkenylzinc
species 53, which could be acylated with benzoyl chloride to
provide enamide 54 in 56% overall yield (Scheme 4). It was
also possible to trap alkenylzinc species 55 derived from
Table 6 presents the results of hydrometalation of
various ynamides with Et2Zn (2 equiv) using [Rh(cod)Cl]2
(2.5 mol %) and (2-Fur)3P (10 mol %). Ynamides contain-
ing oxazolidin-2-one (entries 1-6) and pyrrolidin-2-one
(entry 7) functionalities successfully underwent reaction
with generally reasonable-to-high selectivities in mode-
rate yields. However, separation of the hydrometalation
products from the carbometalation products by chro-
matography proved difficult, and the compounds were
generally isolated as mixtures. Significantly lower selec-
tivity was observed with phenyl-substituted ynamide 1f
(entry 6).
Scheme 2 illustrates a possible catalytic cycle for the
carbozincation reactions. Reaction of Rh(cod)(acac) with
an organozinc reagent would generate organorhodium
species 46. Syn-carbometalation of the ynamide 1 with 46
would then provide alkenylrhodium intermediate 47.39
Presumably, prior coordination of 46 with the carbonyl
group of the ynamide is responsible for the observed
regioselectivity of carbometalation.36 Transmetalation of
alkenylrhodium 47 with a further organozinc species
(R1ZnL) would then regenerate 46 and furnish alkenylzinc
(39) For rhodium-catalyzed conjugate addition of organozinc reagents to
alkynes, see: (a) Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 2071–
2073. (b) Shintani, R.; Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8,
4799–4801.
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SCHEME 4. Electrophilic Trapping of Alkenylzinc Intermediates
SCHEME 5. Sequential Carbozincation-Negishi Coupling
SCHEME 6. Synthesis of Triaryl-Substituted Enamide 62
SCHEME 7. Sequential Hydrozincation-Negishi Coupling
ynamide 1a with allyl bromide to give enamide 56 in 56%
yield.
Alternatively, the alkenylzinc intermediates could be em-
ployed in Pd-catalyzed Negishi reactions40 with aryl, hetero-
aryl, or alkenyl iodides by using Pd2(dba)3 (2.5 mol %) and
(2-Fur)3P (10 mol %) to provide enamides 58 and 59, and
dienamide 60, respectively (Scheme 5). Furthermore, a simi-
lar sequence was possible by using an alkenylzinc species
derived from carbometalation of ynamide 1f with a functio-
nalized arylzinc iodide, and this reaction resulted in the
formation of triaryl-substituted enamide 62, albeit in only
18% yield, along with 20% of the simple carbometalation
product 30 (Scheme 6). The low yield observed in
this transformation is not surprising, given the significant
steric hindrance that must be overcome in the Negishi
reaction.
Finally, functionalization of alkenylzinc species produced
in the hydrometalation manifold was examined (Scheme 7).
Sequential hydrozincation-Negishi coupling40 was per-
formed on ynamides 1a and 1h by using 0.55 equiv of
Et2Zn and two para-substituted aryl iodides to furnish the
R,β-disubstituted enamides 64 and 65, respectively. Yields
were lower than those obtained in the corresponding carbo-
zincation-Negishi process (Scheme 5), as a significant
quantity of the uncoupled hydrometalation product was
observed in both cases. The reasons for the unexpectedly
aCa. 30% of the hydrometalation product 4 was detected in the
unpurified reaction mixture, but was not isolated. bHydrometalation
product 45 was also isolated in 41% yield.
lower efficiency of the sequential hydrozincation-Negishi
process are not known at this time, though a possible
explanation could lie in the altered nature of the rhodium
species in the hydrometalation manifold having a dele-
terious effect on the palladium-catalyzed cross-coupling
reaction.
(40) (a) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42,
1821-1823. For reviews, see: (b) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93,
2117–2188. (c) Negishi, E. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed. John Wiley & Sons: New York, 2002; Vol. 1,
pp 229-247.
To demonstrate the synthetic utility of the enamide products,
further transformations were examined. For example, treatment
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Gourdet et al.
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to provide functionalized cyclohexene 73 with high selectiv-
ity (eq 5).
SCHEME 8. Acid-Catalyzed Cyclization of Enamide 2
of enamide 2 with TMSOTf provided tetrahydrona-
phthalene 68 in 86% yield (Scheme 8). Presumably,
this reaction proceeds via protonation of enamide 2 with
trace TfOH present in TMSOTf,41 Friedel-Crafts cycli-
zation of the pendant phenyl group onto the resultant
N-acyliminium ion 66 via a chairlike transition state with
substituents in pseudoequatorial positions, followed
by proton loss from 67. In similar fashion, enamide 20
was converted into tetrahydronaphthalene 69 in 58%
yield, and in this case, X-ray crystallography allowed
confirmation of the relative stereochemistry of the pro-
duct (eq 3).
Tamaru and co-workers have recently developed a range
of nickel-catalyzed reductive coupling reactions of dienes
with carbonyl compounds that are mediated by triethylbor-
ane or diethylzinc.43 Interestingly, the range of dienes that
are tolerated in these homoallylations include siloxy-1,3-
butadienes.43d These results prompted us to evaluate diena-
mides, a hitherto unexplored group of dienes in these reac-
tions, in an analogous process. We were pleased to observe
that in the presence of catalytic Ni(acac)2 and Et2Zn
(2 equiv), dienamide 22 reacted smoothly with p-anisalde-
hyde in a reductive coupling reaction to provide bis-homo-
allylic alcohol 74 in 74% yield (eq 6).44
Conclusions
In summary, rhodium-catalyzed carbozincations of yna-
mides with diorganozinc reagents or functionalized organo-
zinc halides have been developed, and a study of ligand
effects on the course of the reaction has led to the develop-
ment of a complementary hydrometalation procedure. The
utility of the alkenylzinc intermediates generated in these
processes has been explored in reactions with electrophiles
and in palladium-catalyzed Negishi couplings, resulting in
more highly substituted enamides. These methods enable the
highly regio- and stereoselective synthesis of multisubsti-
tuted enamides and dienamides that would otherwise be
difficult to prepare with alternative methods.
Diels-Alder reactions of dienamides 22 and 23 that were
produced by ynamide carbometalation with divinylzinc
(Table 3, entries 5 and 6) are illustrated in eqs 4 and 5.
Reaction of 22 with N-methyl maleimide (70) proceeded
efficiently in THF at room temperature to provide bicyclic
product 71 in 89% yield with high (>19:1) endo-selectivity
(eq 4).42 Similarly, dienamide 23 reacted with nitroalkene 72
(41) This hypothesis was supported by the following experiments: (i) The
same reaction conducted in the presence of 5 mol % of TfOH provided
tetrahydronaphthalene 68 in 88% yield. (ii) When enamide 2 was treated with
0.5 equiv of TMSOTf in the presence of 1 equiv of 2,6-lutidine, no reaction
was observed.
Experimental Section
General Procedure 1: Carbozincation of Ynamides with Orga-
nozinc Halide Reagents. To a solution of the appropriate
ynamide (1.0 equiv) and Rh(cod)(acac) (0.05 equiv) in THF
(10 mL/mmol of ynamide) at 0 °C was added the appropriate
(42) ForexamplesofDiels-Alder reactions of dienamides, see: (a) Oppolzer,
€
W.; Frostl, W. Helv. Chim. Acta 1975, 58, 590–593. (b) Oppolzer, W.; Bieber, L.;
Francotte, E. Tetrahedron Lett. 1979, 20, 4537–4540. (c) Overman, L. E.; Freerks,
R. L.; Petty, C. B.; Clizbe, L. A.; Ono, R. K.; Taylor, G. F.; Jessup, P. J. J. Am.
Chem. Soc. 1981, 103, 2816-2822. For examples of Diels-Alder reactions of
oxazolidin-2-one-substituted dienamides, see: (d) Murphy, J. P.; Nieuwenhuyzen,
M.; Reynolds, K.; Sarma, P. K. S.; Stevenson, P. J. Tetrahedron Lett. 1995, 36,
9533–9536. (e) McAlonan, H.; Murphy, J. P.; Nieuwenhuyzen, M.; Reynolds, K.;
Sarma, P. K. S.; Stevenson, P. J.; Thompson, N. J. Chem. Soc., Perkin Trans. 1
2002, 69–79. (f) Movassaghi, M.; Hunt, D. K.; Tjandra, M. J. Am. Chem. Soc.
2006, 128, 8126–8127. (g) Movassaghi, M.; Tjandra, M.; Qi, J. J. Am. Chem.
Soc. 2009, 131, 9648–9650.
(43) (a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem. Soc.
1998, 120, 4033–4034. (b) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.;
Shimizu, M.; Matsumoto, S.; Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38,
397–400. (c) Shibata, K.; Kimura, M.; Shimizu, M.; Tamaru, Y. Org. Lett.
2001, 3, 2181–2183. (d) Kimura, M.; Ezoe, A.; Mori, M.; Iwata, K.; Tamaru,
Y. J. Am. Chem. Soc. 2006, 128, 8559–8568.
(44) Addition of an ethyl group to the aldehyde was found to be a
competing pathway with more electrophilic substrates such as benzaldehyde.
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Gourdet et al.
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organozinc halide (2 equiv) over 1 min, and the reaction was
then stirred at room temperature until complete consumption of
starting material was observed by TLC analysis. The reaction
mixture was filtered through a short pad of silica gel with
CH2Cl2 as eluent, and the filtrate was concentrated in vacuo.
Purification of the residue by column chromatography afforded
the desired enamide.
2858, 1753 (CdO), 1671, 1251, 1099, 909, 736 cm-1; 1H NMR
(360 MHz, CDCl3) δ 6.35 (1H, dt, J = 9.7, 1.5 Hz), 4.81 (1H,
dt, J = 9.7, 7.8 Hz), 4.38 (2H, app dd, J = 9.0, 7.0 Hz), 4.02
(2H, app dd, J = 9.0, 7.0 Hz), 3.64 (2H, t, J = 6.5 Hz), 2.39
(2H, dtd, J = 7.8, 6.5, 1.5 Hz), 0.89 (9H, s), 0.05 (6H, s); 13
C
NMR (62.9 MHz, CDCl3) δ 156.8 (C), 123.8 (CH), 110.7
(CH), 62.6 (CH2), 62.2 (CH2), 45.5 (CH2), 30.1 (CH2), 25.9
(3 ꢀ CH3), 18.3 (C), -5.4 (2 ꢀ CH3); HRMS (ES) exact
mass calcd for C13H26NO3Si [M þ H]þ 272.1676, found
272.1677.
3-{1-[1-(2-Oxooxazolidin-3-yl)-meth-(E)-ylidene]-3-phenylpro-
pyl}benzoic Acid Ethyl Ester (28). The title compound was pre-
pared according to general procedure 1 with ynamide 1a (43 mg,
0.20 mmol) and 3-(ethoxycarbonyl)phenylzinc iodide (0.5 M in
THF, 0.80 mL, 0.40 mmol) for a reaction time of 1.5 h and purified
by column chromatography (30% EtOAc/hexane) to give a yellow
oil (55 mg, 75%). Rf 0.18 (30% EtOAc/hexane); IR (film) 2985,
1755 (CdO), 1714 (CdO), 1479, 1404, 1265, 1088, 1043, 908, 735
cm-1; 1H NMR (360 MHz, CDCl3) δ 8.09 (1H, t, J = 1.6 Hz), 7.99
(1H, dt, J = 7.8, 1.4 Hz), 7.59 (1H, ddd, J = 7.8, 1.8, 1.2 Hz), 7.45
(1H, t, J = 7.8 Hz), 7.30-7.26 (2H, m), 7.22-7.18 (1H, m),
7.15-7.12 (2H, m), 6.44 (1H, s), 4.42 (2H, q, J = 7.1 Hz), 4.33
(2H, app dd, J = 8.7, 7.2 Hz), 3.66-3.58 (2H, m), 2.92 (2H, t, J =
7.6Hz),2.68(2H,t,J=7.6Hz),1.43(3H,t,J=7.1 Hz); 13CNMR
(62.9 MHz, CDCl3) δ 166.5 (C), 157.0 (C), 141.2 (C), 140.5 (C),
131.2 (CH), 130.8 (C), 130.0 (C), 128.6 (CH), 128.5 (3 ꢀ CH), 128.4
(2 ꢀ CH), 127.9 (CH), 126.2 (CH), 123.4 (CH), 62.3 (CH2), 61.1
(CH2), 45.9 (CH2), 34.3 (CH2), 31.5 (CH2), 14.3 (CH3); HRMS
(ES) exact mass calcd for C22H27N2O4 [M þ NH4]þ 383.1965,
found 383.1966.
General Procedure 2: Hydrometalation of Ynamides. To a
stirred solution of the appropriate ynamide (1.0 equiv), [Rh(cod)-
Cl]2 (0.025 equiv), and tri(2-furyl)phosphine (0.10 equiv) in
THF (10 mL/mmol of ynamide) at 0 °C was added Et2Zn
(1.0 M in hexane, 2.0 equiv) over 1 min and the reaction was then
stirred at room temperature until complete consumption of starting
material was observed by TLC analysis (up to 6 h). The mixture was
filtered through a short pad of silica gel with CH2Cl2 (30 mL) as
eluent, and the filtrate was concentrated in vacuo. Purification
of the residue by column chromatography afforded the desired
enamide.
(()-(3aS,4S,7aS)-2-Methyl-4-(2-oxooxazolidin-3-yl)-5-phenyl-
3a,4,7,7a-tetrahydroisoindole-1,3-dione (71). To a solution of die-
namide 22 (107 mg, 0.50 mmol) in THF (2.5 mL) was added
a solution of N-methylmaleimide (56 mg, 0.50 mmol) in THF
(2 mL þ 0.5 mL rinse). The mixture was stirred at room tempera-
ture for 40 h and the solvent was removed in vacuo. Purification of
the residue by column chromatography (25% EtOAc/hexanef
75% EtOAc/hexane) gave the Diels-Alder product 71 as a color-
less solid (145 mg, 89%). Rf 0.11 (25% EtOAc/hexane); mp 62-
64 °C;IR(CHCl3) 2974, 1749 (CdO), 1518, 1408, 1344, 1227, 1109,
1
1038, 864, 729 cm-1; H NMR (360 MHz, CDCl3) δ 7.36-7.26
(5H, m), 6.44 (1H, dd, J= 5.5, 3.7 Hz), 5.50 (1H, d, J=7.3 Hz),
4.09-4.04 (2H, m), 3.50 (2H, dd, J=9.7, 7.3 Hz), 3.29-3.20 (2H,
m), 3.09 (1H, ddd, J=8.2, 8.1, 6.3 Hz), 3.01 (3H, s), 2.87-2.70 (2H,
m); 13CNMR(62.9MHz, CDCl3) δ179.3 (C), 175.9 (C), 158.0 (C),
138.1 (C), 134.4 (C), 128.9 (2 ꢀ CH), 128.1 (CH), 127.5 (CH), 125.5
(2 ꢀ CH), 61.9 (CH2), 48.5 (CH), 43.6 (CH), 43.3 (CH2), 37.0
(CH), 24.7 (CH3), 22.6 (CH2); HRMS (ES) exact mass calcd for
C18H18N2O4Na [M þ Na]þ 349.1159, found 349.1158.
Acknowledgment. This work was supported by the Euro-
pean Commission (Project No. MEST-CT-2005-020744),
GlaxoSmithKline, and the University of Edinburgh. The
EPSRC National Mass Spectrometry Service Centre at the
University of Wales, Swansea is thanked for providing high-
resolution mass spectra. We thank Charles W. Parry for
preliminary experiments, and Nicholas P. Funnell and
Dr. Fraser J. White for assistance with X-ray crystallography.
3-[(Z)-4-(tert-Butydimethylsilyloxy)but-1-enyl]oxazolidin-2-
one (42). The title compound was prepared according to
general procedure 2 from ynamide 1d (133 mg, 0.50 mmol)
for a reaction time of 2 h and purified by column chromato-
graphy (15% EtOAc/hexane) to give a yellow oil (79 mg,
58%). Rf 0.40 (30% EtOAc/hexane); IR (film) 2956, 2929,
Supporting Information Available: Detailed experimental
procedures, spectroscopic data for new compounds, and crystal-
lographic data in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
7858 J. Org. Chem. Vol. 74, No. 20, 2009