Palladium-catalyzed intramolecular α-arylation of α-amino acid esters

Article abstract of DOI:10.1021/jo0107756

The Pd-catalyzed intramolecular α-arylation of α-amino acid esters is described. Starting from readily available amino acids, the synthesis of a variety of isoindolines and tetrahydroisoquinoline carboxylic acid esters has been accomplished. Additionally, fused tricyclic systems can be efficiently prepared from cyclic amino acid esters. Reaction conditions have been found that allow the use of tert-butyl ester and N-(benzyloxycarbonyl) protecting groups.

Full text of DOI:10.1021/jo0107756

J . Org. Chem. 2002, 67, 465-475
465
P a lla d iu m -Ca ta lyzed In tr a m olecu la r r-Ar yla tion of r-Am in o Acid
Ester s
Oliver Gaertzen and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received J uly 31, 2001
The Pd-catalyzed intramolecular R-arylation of R-amino acid esters is described. Starting from
readily available amino acids, the synthesis of a variety of isoindolines and tetrahydroisoquinoline
carboxylic acid esters has been accomplished. Additionally, fused tricyclic systems can be efficiently
prepared from cyclic amino acid esters. Reaction conditions have been found that allow the use of
tert-butyl ester and N-(benzyloxycarbonyl) protecting groups.
In tr od u ction
the literature for the synthesis of R-aryl esters.13 Hartwig
recently disclosed a successful palladium-catalyzed inter-
and intramolecular R-arylation of amides using a variety
of aryl bromides and chlorides.14-16 Musco and Santi
reported a palladium-mediated coupling of trimethylsi-
lylketene acetals in the presence of thallium acetate to
provide 2-(aryl) alkyl esters in moderate to good yields.17,18
Yamanaka disclosed a palladium-catalyzed synthesis of
coupling of aryl halides and ethoxy(trialkylstannyl)-
acetylenes that provided 2-(aryl)ethyl acetates after an
additional solvolysis step.19,20 Kuwajima described that
in situ generated tin enolates undergo palladium-
catalyzed cross-coupling with aryl bromides to provide
R-aryl ketones.21 Sulikowski extended this method to the
synthesis of aryl acetates in good yield by palladium-
catalyzed cross-coupling of aryl bromides and copper(II)
enolates.22 Recently, a general method for the arylation
of esters employing a wide variety of different aryl
bromides and clorides has been developed in our labo-
ratories.23,24 In this case, the ester enolate was prepared
in the presence of aryl halide and a palladium catalyst
derived from Pd(OAc)2 and biaryl-based, bulky, electron-
rich phosphine ligands 1 and 2 (Figure 1).
The synthesis of R-arylated carbonyl compounds has
traditionally been a difficult transformation. Recent
advances, especially in the area of palladium-catalyzed
enolate arylation of ketones, have led to the development
of a simple and reliable method for conducting this
reaction intermolecularly.1-7 Moreover, efficient protocols
for both asymmetric arylation8 and vinylation9 of ketone
enolates have been established.
Along with ketone arylation, the R-arylation of esters
and amides is of particular interest. For example, R-aryl
carboxylic acids are integral structural components of
several pharmaceuticals such as ibuprofen and naprox-
en,10 and R-aryl amides have potential medicinal applica-
tions.11,12 In contrast to ketones, there are no regioselec-
tivity issues to consider, but the lower reactivity and the
relative instability of the ester moiety under basic
conditions makes enolization a more challenging task.
As a result, very few practical examples can be found in
(1) Palucki, M.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 11108.
(2) Old, D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1998,
120, 9722.
The direct arylation of R-amino acids constitutes the
most efficient method for the preparation of arylglycines.
Very recently, Hartwig reported the direct arylation of a
protected glycine via Pd catalysis.24,25 Other reports
detailing the direct arylation of unprotected or (protected)
(3) Fox, J . M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J . Am. Chem.
Soc. 2000, 122, 1360.
(4) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem.,
Int. Ed. 1997, 36, 1740.
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Chem. Soc. J pn. 1998, 71, 2239.
(6) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119,
12382.
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1473.
(8) A° hman, J .; Wolfe, J . P.; Troutman, M. V.; Palucki, M.; Buchwald,
S. L. J . Am. Chem. Soc. 1998, 120, 1918.
(13) A more detailed survey of methods to prepare R-aryl esters is
given in ref 3.
(14) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J . F. J . Org.
Chem. 1998, 63, 6546.
(9) Chieffi, A.; Kamikawa, K.; A° hman, J .; Fox, J . M.; Buchwald, S.
L. Org. Lett. 2001, 3, 1897.
(15) Lee, S.; Hartwig, J . F. J . Org. Chem. 2001, 66, 3402.
(16) Culkin, D. A.; Hartwig, J . F. J . Am. Chem. Soc. 2001, 123, 5816.
(17) Carfagna, C.; Musco, A.; Sallese, G.; Santi, R.; Fiorani, T. J .
Org. Chem. 1991, 56, 261.
(18) Galarini, R.; Musco, A.; Pontellini, R.; Santi, R. J . Mol. Catal.
1992, 72, L11.
(19) Sakamoto, T.; Kondo, Y.; Masumoto, K.; Yamanaka, H. Het-
erocycles 1993, 36, 2509.
(20) Sakamoto, T.; Kondo, Y.; Masumoto, K.; Yamanaka, H. J . Chem.
Soc., Perkin Trans. 1 1994, 235.
(21) Kuwajima, I.; Urabe, H. J . Am. Chem. Soc. 1982, 104, 6831.
(22) Agnelli, F.; Sulikowski, G. A. Tetrahedron Lett. 1998, 39, 8807.
(23) Moradi, W. A.; Buchwald, S. L. J . Am. Chem. Soc. 2001, 123,
7996.
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123, 8410.
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H.; Mouzin, G. Tetrahedron 1986, 42, 4095. (b) Sonawane, H. R.; Bellur,
N. S.; Ahuja, J . R.; Kulkarni, D. G. Tetrahedron: Asymmetry 1992, 3,
163 and references therein; (c) Stahly, G. P.; Starrett, R. M. In
Production Methods for Chiral Nonsteroidal Antiinflammatory Profen
Drugs, in Chirality in Industry II; Collins, A. N., Sheldrake, G. N.,
Crosby, J ., Eds.; Wiley: New York, 1997; p 22. (d) Brunner, H.;
Schmidt, P. Eur J . Org. Chem. 2000, 11, 2119 and references therein.
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10.1021/jo0107756 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/28/2001

466 J . Org. Chem., Vol. 67, No. 2, 2002
Gaertzen and Buchwald
F igu r e 1.
glycine derivatives utilize stoichiometric amounts of toxic
aryl lead,26 aryl bismuth,27 or chromium arene com-
plexes.28
F igu r e 2.
ing interesting cytostatic, antineoplastic, and antiviral
activity. Moreover, 4 and 5 can be regarded as a novel
type of conformationally restricted amino acids, which
are potentially interesting for medicinal and peptide
chemistry.42,43
Among other methods,44,45 common synthetic pathways
for the synthesis of tetrahydroisoquinoline carboxylic
acids involve hydrogenations of benzo-fused cyclic imines
and Pictet-Spengler-type reactions.46,47 Both methods,
however, require reasonably complex precursor com-
pounds, and the synthesis of quarternary carbon centers
adjacent to the carboxylic acid is difficult and requires
the use of highly reactive R-ketoacid derivatives.48,49 In
the case of unsymmetrically substituted arenes, regiose-
lectivity is often a problem with these Mannich-type
cyclizations.50,51
Although a fair amount of attention has been paid to
intermolecular versions of carbonyl enolate arylations,
less work has been reported on intramolecular variants.
In 1988, Ciufolini published the first Pd-catalyzed in-
tramolecular arylation of 1,3-dicarbonyl compounds at
high temperature using Ph3P as a ligand.29 With less
activated esters, however, the yields are generally low.
Muratake reported the intramolecular R-arylation of
aldehydes, ketones, and nitroalkanes to form five- to
seven-membered rings in reasonable to good yields.30-32
In some cases, aryl halide reduction was observed in up
to 29% yield. Piers developed a method for the intramo-
lecular vinylation of ketones, which was successfully
employed in the synthesis of (()-crinipellin B.33,34 Later,
the method was used by Sole´ and Bonjoch for the
synthesis of bridged azabicyclic compounds.35 Recently,
Reissig reported a few cases of intramolecular ketone
arylation to form indanes, albeit in low yield.36 Finally,
Hartwig accomplished the Pd-catalyzed synthesis of
2-oxoindoles in high yields using either BINAP,14 Cy3P,
or a chiral carbene15 as ligands. Attempts to apply this
method to the synthesis of benzo-δ-lactams resulted in
low yields.14 To our knowledge, only one successful
example of a Pd-catalyzed intramolecular R-arylation of
amides to form a fused six-membered ring lactam has
been reported as a key step employed in the synthesis of
cherylline and latifine.37
Medicinal groups have recently reported increasing
interest in dihydroisoindole derivatives, which is reflected
in a number of patents52 and publications dealing with
a variety of medicinal applications.53 In contrast, the
development of efficient methods for the synthesis of
substituted dihydroisoindoles seems to be a neglected
area of research, and very few publications can be found
in the literature.54 Common methods for the synthesis
of 1,3-unsubstituted dihydroisoindoles are the metal-
catalyzed55-58 or base-induced59 [2 + 2 + 2] cocyclizations
of bispropargylamines with alkynes. Another method
employed an intramolecular Diels-Alder reaction to
Dihydroisoindole and tetrahydroisoquinoline carboxylic
acids (4, 5, Figure 2) are common structural motifs in
pharmaceuticals and natural products such as Tetrazo-
mine,38 Bioxalomycin,39 Excentricine40,41 or the Erythrina
alkaloids cocculine and erytrosine, some of them exhibit-
(42) Hanessian, S.; McNaughtonSmith, G.; Lombart, H. G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789.
(43) Ishida, H.; Inoue, Y. Rev. Heteroatom Chem. 1999, 19, 79.
(44) Kametani, T. In Chem. Heterocycl. Comput.; Grethe, G., Ed.;
Wiley-Interscience: New York, 1981; Vol. 38(1), p 170.
(45) Popp, F. D.; Duarte, F. F. In Chem. Heterocycl. Comput.;
Kathawala, F. G., Coppola, G. M., Schuster, H. F., Eds.; Wiley-
Interscience: New York, 1990; Vol. 38(2), p 245.
(46) Whaley, W. M.; Govindachari, T. R. Org. React. (N.Y.) 1951, 6,
151.
(47) Herberich, B.; Kinugawa, M.; Vazquez, A.; Williams, R. M.
Tetrahedron Lett. 2001, 42, 543.
(48) Kapadia, G. J .; Rao, G. S.; Hussain, M. H.; Chowdhuri, B. K.
J . Heterocycl. Chem. 1973, 10, 135.
(49) Kawai, M.; Deng, Y.; Kimura, I.; Yamamura, H.; Araki, S.; Naoi,
M. Tetrahedron: Asymmetry 1997, 8, 1487.
(50) Kametani, T.; Ujiie, A.; Ihara, M.; Fukumoto, K.; Lu, S.-T. J .
Chem. Soc., Perkin Trans. 1976, 1218.
(51) Ishiwata, S.; Itakura, K. Chem. Pahrm. Bull. 1970, 18, 896.
(52) For recent examples, see: (a) Elliott, J . D.; Franz, R. G.; Lago,
M. A.; Gao, A. U.S. Patent 5,929,106, 1999. (b) Elliott, J . D.; Franz, R.
G.; Lago, M. A.; Gao, A. U.S. Patent 5,736,564, 1998. (c) Elliott, J . D.;
Franz, R. G.; Lago, M. A.; Gao, A. World Patent 9,535,107, 1995.
(53) For biological activity, see ref 47 and: (a) Linden, M.; Hadler,
D.; Hofmann, S. Hum. Psychopharmacol. 1997, 12, 445. (b) Kondo, T.;
Yoshida, K.; Yamamoto, N.; Tanayama, S. Arzneim. Forsch. 1996, 46,
11.
(54) For a recent example see: Kukkola, P. J .; Bilci, N. A.; Ikeler,
T. J . Tetrahedron Lett. 1996, 37, 5065.
(55) Chiusoli, G. P.; Pallini, L.; Terenghi, G. Transition Met. Chem.
1983, 8, 189.
(25) For a review on the asymmetric preparation of arylglycines,
see: (a) Williams, R. M.; Hendrix, J . A. Chem. Rev. 1992, 92, 889. For
selected recent references, see: (b) Sigman, M. S.; J acobsen, E. N. J .
Am. Chem. Soc. 1998, 120, 5315. (c) Sigman, M. S.; J acobsen, E. N. J .
Am. Chem. Soc. 1998, 120, 4901. (d) Reddy, K. L.; Sharpless, K. B. J .
Am. Chem. Soc. 1998, 120, 1207.
(26) Chaari, M.; J enhi, A.; Lavergne, J .-P.; Viallefont, P. Tetrahedron
1991, 47, 4619.
(27) O’Donnell, M. J .; Bennett, W. D.; J acobsen, W. N.; Y., M.
Tetrahedron Lett. 1989, 30, 3909.
(28) Chaari, M.; Lavergne, J .-P.; Viallefont, P. Synth. Commun.
1989, 19, 1121.
(29) Ciufolini, M. A.; Qi, H.-B.; Browne, M. E. J . Org. Chem. 1988,
53, 4149.
(30) Muratake, H.; Hayakawa, A.; Natsume, M. Tetrahedron Lett.
1997, 38, 7577.
(31) Muratake, H.; Nakai, H. Tetrahedron Lett. 1999, 40, 2355.
(32) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581.
(33) Piers, E.; Marais, P. C. J . Org. Chem. 1990, 55, 3454.
(34) Piers, E.; Renaud, J . J . Org. Chem. 1993, 58, 11.
(35) Sole´, D.; Peidro´, E.; Bonjoch, J . Org. Lett. 2000, 2, 2225.
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R-Arylation of R-Amino Acid Esters
J . Org. Chem., Vol. 67, No. 2, 2002 467
generate isoindolines with different N substituents.60
A
carboxylic acid esters, and the results are summarized
in Tables 1 and 2.
simple and straightforward strategy involves the alky-
lation of primary amines with 1,2-bisbenzyl halides to
give isoindolines.61 Further functionalization in the 1- or
3-position is feasible; however, no regioselective trans-
formations have been reported. Alternatively, substituted
oxoindoles can be reduced to the corresponding mono-
substituted dihydroisoindoles.62
The lack of a general method for the synthesis of
substituted isoindolines prompted us to explore the
palladium-catalyzed intramolecular R-arylation of amino
acid esters based on our previous success in R-arylation
processes. Starting from readily available R-amino acid
esters, our research was aimed to provide a general and
efficient protocol for the regioselective synthesis of tet-
rahydroisoquinoline and dihydroisoindole carboxylic acid
derivatives. In addition, synthetic efforts were aimed
toward the synthesis of cyclic aryl-substituted amino
acids bearing quarternary carbon centers.
As shown in Tables 1 and 2, the formation of five- and
six-membered rings can be carried out in high yield. A
small amount, ca. 3%, of reduced aryl halide was ob-
served in some cases. Using electron-rich bromoarenes,
cyclization could still be accomplished in good yield albeit
with longer reaction times (Table 1, entry 2; Table 2,
entries 2 and 6). As shown in Tables 1 and 2, the
formation of six-membered rings proceeds more slowly
than five-membered rings and requires the more active
catalyst based on ligand 3. Under similar reaction
conditions, ligand 3 provided increased reaction rates and
yields compared to previous reactions employing ligand
2 or Ph3P (Table 2, entries 3-5).
We also examined the effect of steric hindrance at the
enolate carbon. We found that a hydrogen or a methyl
group is well tolerated resulting in very good yields. In
general, tertiary centers are easier to form than quar-
ternary centers, thus resulting in shorter reaction times
(Tables 1 and 2, entries 1 and 3). With an isopropyl
substituent, higher catalyst loading, higher reaction
temperatures and longer reaction times are required.
Additionally, a significant amount of aryl halide reduc-
tion is observed (Table 1, entry 5). A remarkable excep-
tion is the phenylglycine-derived compound (Table 1,
entries 6-9); the reaction proceeds quantitatively in 2 h
at 90 °C, and the reaction can be conducted at 50 °C or
even without a ligand at 90 °C, although longer reaction
times are required.
For the synthesis of fused heterocyclic systems, cy-
clization precursors have been readily prepared from
proline and pipecolinic acid esters (Table 1, entries 10-
13, and Table 2, entries 7-9, respectively). The cycliza-
tion proceeds smoothly to give tricyclic compounds with
various ring sizes in very good yields. The use of 2 and 3
is preferred over Cy3P. Ligand 2 gives the tricyclic
aminoesters in good yield (Table 1, entries 10 and 12),
while the trialkylphosphine gives lower yield (Table 1,
entry 11) and lower reaction rates, respectively (Table
1, entry 13). Interestingly, azatricycle 17 shows a sig-
nificant increase of polarity (as judged by TLC) compared
to the precusor compound 16, presumably due to fixed
geometry of the aza[3.3.0] ring system. It should be noted
that compounds 17, 19, 29, and 31 resemble the core
structures of several alkaloids (vide infra).
The use of common amine protecting groups in pal-
ladium-catalyzed ring formation is of interest. Thus, we
prepared N-(benzyloxycarbonyl) (Cbz) protected amino
acid esters to briefly investigate whether the protecting
group can survive under the chosen reaction conditions.
The Cbz and tert-butyl ester represent an orthogonal set
of protecting groups so that it is possible to selectively
liberate the desired functionality while the other main-
tains unaffected.66,67 As shown in Table 3, both alanine
and phenylglycine derived compounds give the desired
product in good yield. Again, 3 was the ligand of choice
in this series of transformations.
Resu lts a n d Discu ssion
Our initial experiments in intramolecular enolate
arylation were carried out with 2-(2-bromobenzyloxy)
acetic acid tert-butyl ester63 screening a variety of bases
and solvents. As ligands, we chose simple triaryl- or
trialkylphosphines such as Ph3P and Cy3P as well as
biaryl-based, sterically hindered phosphines 2 and 3
(Scheme 1) which are commercially available64 or readily
accessible by a one-pot procedure recently developed in
our laboratories.65 It was found that catalysts based on
ligands 2 and 3 are superior to other simple commercially
available phosphines in both yield and reaction rate.
Initially, we chose to use 2.3 mol % Pd2(dba)3 and a
slight excess of either ligand 2 or 3 (5 mol %) as
precursors for the active catalyst; reactions with Pd(OAc)2
gave inferior results. The use of NaHMDS or LiHMDS
in toluene, conditions which have been successfuly em-
ployed in ester arylation,23 resulted in decomposition of
starting material, presumably due to unselective Claisen
condensation reactions. Weak bases such as K3PO4 or Cs2-
CO3 led to no conversion at all, whereas LiO-t-Bu in
dioxane accomplished the desired cyclization in good
yield. It should be noted that NaO-t-Bu in dioxane led to
inferior results. Other solvents such as toluene, THF or
DME in combination with LiO-t-Bu gave no or little
cyclization product. It was also found that tert-butyl
esters provide the best results under these reaction
conditions. While all cyclization reactions have been
conducted under an argon atmosphere, they are easy to
perform. Ligands and reagents were usually kept in a
desiccator and stored and weighed in the air, thus
making the reaction setup very simple. The optimized
reaction conditions were successfully employed for the
synthesis of dihydroisoindole and tetrahydroisoquinoline
(60) Hernandez, J . E.; Fernandez, S.; Arias, G. Synth. Commun.
1988, 18, 2055.
(61) For a more recent example, see: Berger, D.; Citarella, R.; Dutia,
M.; Greenberger, L.; Hallett, L.; Paul, R.; Powell, D. J . Med. Chem.
1999, 42, 2145.
(62) Couture, A.; Deniau, E.; Ionescu, D.; Grandclaudon, P. Tetra-
hedron Lett. 1998, 39, 2319.
(63) Gaertzen, O., Buchwald, S. L. Unpublished results.
(64) 2-(Dicyclohexylphosphinyl)-2′-(N,N-dimethylamino)biphenyl 2
In flu en ce of Ba se, Liga n d , a n d P a lla d iu m Sou r ce.
A brief comparison of ligands (see Tables 1 and 2) has
shown that the more sterically hindered, biphenyl-based
and 2-(diphenylphosphinyl)-2′-(N,N-dimethylamino)biphenyl
available from Strem Chemicals, Inc.
3
are
(66) Kocienski, P. J . Protecting Groups; Thieme Verlag: Stuttgart,
New York, 1994.
(65) Tomori, H.; Fox, J . M.; Buchwald, S. L. J . Org. Chem. 2000,
65, 5334.
(67) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.

468 J . Org. Chem., Vol. 67, No. 2, 2002
Ta ble 1. Syn th esis of Dih yd r oisoin d ole Ca r boxylic Acid Ester s
Gaertzen and Buchwald
a
b
Isolated yields are an average of at least two runs. 3.8 mol % Pd2(dba)3 and 8 mol % ligand were used, and ca. 8% of reduced arene
was formed. c The GC yield was determined using dodecane as an internal standard. The reaction was not allowed to go to completion.
d
e GC yield; the reaction proceeded to 91% conversion. f GC yield; the reaction proceeded to 69% conversion, and 5% arene reduction was
g
observed. GC yield; the reaction proceeded to 71% conversion.
ligands 2 and 3 are superior to other simple trialkyl or
triaryl phosphines such as Cy3P and Ph3P, respectively.
Although in some cases good results have been achieved
using Cy3P as ligand (Table 1, entries 4 and 11), 2 and 3
have been shown to be both more effective and more
general for the cyclization reaction. This may be related
to the fact that the biphenyl backbone provides a weak
coordination site to the metal via either the amino group
or the arene itself.68 Increased reactivity of catalysts
based on 3 relative to those using 2 was observed in
several cases. For most reactions, the use of 2 results in
a very clean reaction. In contrast, with more active ligand
3 the formation of minor side products was observed. The
decreased steric demand of ligand 3 relative to 2 may be
important in these cyclizations. Additionally, ligand 3 is
less electron-rich than 2. Thus, the intermediate Pd(II)
complex would be of enhanced elecrophilicity at the Pd
center, which might affect rate and efficiency of its
reaction with the enolate. At present, the deconvolution
of the relative steric and electronic effects that make 3
the ligand of choice in the cyclization of sterically
demanding substrates such as 12 (vide infra) is not
straightforward.
The best results in the cyclization reactions have been
achieved using a slight excess of either ligand 2 or 3
together with Pd2(dba)3. The use of Pd(OAc)2 gave inferior
results. It is possible that the dibenzylideneacetone acts
as a supporting ligand.69 Alternatively, the R-carboalkoxy-
alkylpalladium intermediates may be resistant to â-hy-
dride elimination and thus do not provide a suitable
reducing agent to generate the requisite catalyst.
It was shown that the type of base plays an important
role in the deprotonation process. Strong amide bases
such as LiHMDS and NaHMDS led to decomposition of
starting material. LiO-t-Bu in dioxane gave the best
results in all cases, whereas the corresponding NaO-t-
Bu led to inferior results. Assuming similar base strength,
this indicates that the counterion plays a decisive role
in the deprotonation step. In addition to the effect of the
R-nitrogen, the Li+ may form a chelating five-membered
ring enolate, thus facilitating deprotonation.70 With ad-
ditional anion-stabilizing groups adjacent to the reactive
(69) For leading references of related work in this area, see: (a)
Amatore, C.; Broeker, G.; J utand, A.; Khalil, F. J . Am. Chem. Soc.
1997, 119, 5176. (b) Tschoerner, M.; Pregosin, P. S.; Albinati, A.
Organometallics 1999, 18, 670.
(70) For similar effects where six-membered ring chelates with Li
facilitate R-deprotonation, see: Blanchette, M. A.; Choy, W.; Davis. J .
T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron
Lett. 1984, 25, 2183 and references therein.
(68) Wolfe, J . P.; Tomori, H., Sadighi, J . P.; Yin, J .; Buchwald, S. L.
J . Org. Chem. 2000, 65, 1158.

R-Arylation of R-Amino Acid Esters
J . Org. Chem., Vol. 67, No. 2, 2002 469
Ta ble 2. Syn th esis of Tetr a h yd r oisoqu in olin e Ca r boxylic Acid Ester s
a
b
Isolated yields are an average of at least two runs. The reaction was not allowed to go to completion. c GC yield; the reaction proceeded
d
to 71% conversion. GC yield; the reaction proceeded to 46% conversion, and ∼7% of arene reduction was observed.
Ta ble 3. Syn th esis of Cbz-P r otected Dih yd r oisoin d ole
Ca r boxylic Acid Ester s
a number of substituents at the enolate center including
phenyl or bulky isopropyl groups has been accomplished.
In addition, the synthesis of fused tricyclic systems
bearing a bridgehead nitrogen has been demonstrated.
A number of different N-substituents including alkyl,
aryl, or carboxyl groups can be employed. This method
is a useful extension of existing R-arylation processes and
provides a simple pathway to substituted dihydroisoin-
doles and other complex non-natural R-amino acids.
Initial results have shown that the reaction protocol is
not limited to the synthesis of N-heterocycles. Investiga-
tions to develop intermolecular variants as well as
asymmetric versions of this reaction are currently un-
derway.
a
2 equiv of LiO-t-Bu, dioxane (0.2 M), 2.3% Pd2(dba)3, L/Pd )
b
1.1. Isolated yields are an average of at least two runs.
center, an increased rate and quantity of deprotonation
should result. This is consistent with an observation on
the cyclization of the phenylglycine precursor 14 (Table
1, entries 6-9).
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All reactions were carried out
in oven-dried glassware that was placed under vacuum while
hot and cooled under argon. Flash chromatography was
performed on Silicycle ultrapure silica gel (230-400 mesh).
Elemental analyses were performed by Atlantic Microlabs,
Inc., Norcross, GA. Dichloromethane, ether, THF, and toluene
were purchased from J . T. Baker in CYCLE-TAINER solvent
delivery kegs and vigorously purged with argon for 2 h. The
solvents were further purified by passing it through two
packed columns of neutral alumina and copper(II) oxide under
argon pressure.71,72 Dioxane and dodecane (used as internal
Con clu sion
A simple and flexible route to dihydroisoindole and
tetrahydroisoquinoline carboxylic acid derivatives has
been developed that uses the palladium-catalyzed in-
tramolecular R-arylation of R-amino acid esters as the
key step. The cyclization precursors are easily synthe-
sized from commercially or otherwise readily available
R-amino acids, followed by alkylation or acylation. We
have demonstrated that the palladium-catalyzed cycliza-
tion proceeds smoothly to yield benzo-fused five- and six-
membered heterocycles in good to excellent yields. The
construction of quaternary carbon centers that tolerate
(71) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518.
(72) Alaimo, P. J .; Peters, D. W.; Arnold, J .; Bergman, R. G. J . Chem.
Ed. 2001, 78, 64.

470 J . Org. Chem., Vol. 67, No. 2, 2002
Gaertzen and Buchwald
standard) were purchased in small SureSeal-bottles from
Aldrich Chemical Co. and used as received. Palladium acetate,
tris(dibenzylideneacetone)dipalladium(0), sodium hexameth-
yldisilazane (NaHMDS), and lithium tert-butoxide (LiO-t-Bu)
were purchased from Strem Chemical, Inc. Sodium tert-
butoxide (NaO-t-Bu) was purchased from Aldrich Chemical Co.
The bases were stored under nitrogen in a Vacuum Atmo-
spheres glovebox, and small samples were taken out, stored
in a desiccator on the bench, and replaced every 2 weeks. All
materials were weighed in the air, except for NaHMDS, which
was weighed and added to the reaction flask in a glovebox. IR
spectra reported in this paper were obtained by placing neat
samples directly on the DiComp probe of an ASI REACTIR in
situ IR instrument. Alternatively, IR spectra for several
compounds were recorded on a Perkin-Elmer FT-IR 1600.
Mass spectra were taken using an Agilent GC-MS, and high-
resolution mass spectra were obtained using a Bruker DAL-
TONICS APEX, 3 T, FT-ICR-MS (Fourier transform ion
cyclotron resonance mass spectrometer), with electrospray ion
source (ESI). Yields in the tables refer to the isolated yields
of compounds estimated to be g95% pure as determined by
1H NMR, GC, and combustion analysis. Melting points were
taken with a MEL TEMP apparatus. Compounds that are
described more than once in the same table were completely
characterized once. Other samples of these compounds were
characterized by comparing their 1H NMR spectra to those of
the fully characterized product, and their purity was confirmed
by GC analysis.
2-P h en yl-2,3-d ih yd r o-1H-isoin d ole-1-ca r boxylic Acid
ter t-Bu tyl Ester (7) (Ta ble 1, En tr y 1). Following the
general procedure, 6 (0.188 g, 0.5 mmol) in dioxane (2.5 mL)
was allowed to react for 1 h at 85 °C using ligand 2. Flash
column chromatography (ether/hexanes 1:15) yielded 7 as a
pale yellow oil (0.115 g, 0.39 mmol, 78%) that solidified upon
storage. Mp: 72 °C. 1H NMR (C6D6, 400 MHz) δ: 7.47-7.41
(m, 1H), 7.32-7.26 (m, 2H), 7.10-7.03 (m, 2H), 6.97-6.91 (m,
1H), 6.86-6.81 (m, 1H), 6.70-6.55 (m, 2H), 5.36-5.33 (d, 1H,
J ) 3.5 Hz), 4.59-4.53 (dd, 1H, J ) 3.5, 12.9 Hz), 4.36-4.31
(d, 1H, J ) 12.9 Hz), 1.19 (s, 9H). 13C NMR (C6D6, 100 MHz)
δ: 171.2, 146.9, 139.1, 138.0, 130.0, 128.7, 127.8, 123.4, 123.0,
117.7, 112.8, 81.5, 68.3, 57.8, 54.3, 28.1 ppm. IR (CH2Cl2, cm-1
)
ν: 3043, 2979, 2933, 2875, 2840, 1740, 1603, 1505, 1468, 1368,
1146, 1094, 1036, 1003, 955, 839, 750, 690. Anal. Calcd for
C
19H21NO2: C, 77.26; H, 7.17. Found: C, 77.12; H, 7.17.
N-P h en yl-6-br om over a tr yla m in e. (a) 6-Bromoveratryl-
amine (0.98 g, 4 mmol) and aniline (0.37 mL, 4 mmol) were
dissolved in dichloromethane (12 mL), and MgSO4 (1 g) was
added. The slurry was stirred for 1 h at ambient temperature,
the MgSO4 was filtered off, and the solvent was removed under
reduced pressure. The crude imine was taken up in MeOH
(16 mL), acetic acid (0.34 mL, 6 mmol) and NaCNBH3 (0.25 g,
4 mmol) were added, and the mixture was stirred overnight.
Water and solid sodium bicarbonate were added, the aqueous
layer was extracted four times with ether, and the combined
organic layers were dried over MgSO4 and concentrated in
vacuo. The crude product was purified by flash column
chromatography (ether/hexanes 1:8) yielding the title com-
pound as a white solid (1.25 g, 3.87 mmol, 97%). Mp: 86 °C.
1H NMR (C6D6, 400 MHz) δ: 7.16-7.06 (m, 2H), 6.94 (s, 1H),
6.77 (s, 1H), 6.76-6.70 (m, 1H), 6.45-6.49 (m, 1H), 4.17-4.12
(s+s, 2H), 3.50 (s, 1H), 3.22 (s, 3H), 2.97 (s, 3H). 13C NMR
(C6D6, 100 MHz) δ: 150.1, 150.0, 148.7, 131.0, 129.9, 118.4,
116.6, 113.6, 113.3, 113.0, 55.9, 55.8, 48.7 ppm. IR (CH2Cl2,
cm-1) ν: 3415, 3010, 2962, 2937, 2842, 1603, 1501, 1465, 1437,
1385, 1314, 1256, 1208, 1156, 1030, 955, 864, 799, 754, 692.
Anal. Calcd for C15H16BrNO2: C, 55.92; H, 5.01. Found: C,
56.06; H, 5.09.
N-(2-Br om o-4,5-d im eth oxyben zyl)-N-p h en yl ter t-Bu tyl
Aceta te 8. A round-bottomed flask was charged with 6-bromo-
N-(methyl)veratrylamine (1.24 g, 3.87 mmol), 2-bromo-tert-
butyl acetate (0.575 mL, 4.25 mmol), NaOAc (0.35 g, 4.25
mmol) and dry ethanol (0.5 mL), purged with argon and stirred
for 6 h at 75 °C. After the mixture was cooled to room
temperature, water and ether were added, the aqueous layer
was extracted three times with ether, and the combined
organic layers were washed with aqueous sodium bicarbonate
and brine and dried over MgSO4. The solvent was removed,
and the crude product was purified by flash column chroma-
tography (ether/hexanes 1:8) to yield 8 as an orange oil (0.86
g, 2.06 mmol, 54%) that solidified upon storage. Mp: 91 °C.
1H NMR (C6D6, 400 MHz) δ: 7.18 (s, 1H), 7.14-7.09 (m, 2H),
6.97 (s, 1H), 6.75-6.70 (m, 1H), 6.70-6.56 (m, 2H), 4.56 (s,
2H), 3.71 (s, 2H), 3.33 (s, 3H), 3.20 (s, 3H), 1.30 (s, 9H). 13C
NMR (C6D6, 100 MHz) δ:_170.3, 150.5, 150.2, 149.2, 130.1,
129.9, 128.3, 118.5, 116.9, 113.4, 113.0, 112.6, 81.3, 57.7, 56.1,
56.0, 54.6, 28.4 ppm. IR (CH2Cl2, cm-1) ν: 2979, 2937, 2842,
1740, 1602, 1503, 1465, 1439, 1383, 1370, 1349, 1256, 1221,
1210, 1150, 1030, 951, 849, 800, 754, 692. Anal. Calcd for
Gen er a l Rea ction P r oced u r e for th e Cycliza tion of
R-Am in o Acid Ester s. An oven-dried resealable Schlenk tube
containing a stir bar was evacuated and purged with argon
while cooling to ambient temperature. The Schlenk tube was
charged with 2.0 equiv of LiO-t-Bu, 2.25 mol % of Pd2(dba)3,-
and 5 mol % of either 2-(dicyclohexylphosphinyl)-2′-(N,N-
dimethylamino)biphenyl (2) or 2-(diphenylphosphinyl)-2′-(N,N-
dimethylamino)biphenyl (3). The reaction vessel was evacu-
ated and backfilled again with argon, and three-fourths of the
dioxane was added via syringe under argon. The mixture was
stirred for 5 min at room temperature, followed by addition of
a solution of dodecane (0.045 mL, 0.2 mmol) and 1 equiv of
the cyclization precursor in the remaining dioxane via syringe.
The solution was 0.2 M in dioxane as solvent. The Schlenk
tube was sealed and placed in a preheated oil bath at the given
temperature for the time indicated. After the reaction was
complete, as judged by either GC or TLC analysis, the reaction
mixture was cooled to ambient temperature. The crude
mixture was filtered through a silica gel plug which was
washed thoroughly with ether. The solution was concentrated
and further purified by flash column chromatography.
N-(2-Br om oben zyl)-N-p h en yl ter t-Bu tyl Aceta te (6).
2-Phenylaminoacetic acid tert-butyl ester73 (1.04 g, 5 mmol)
was dissolved in DMF (4 mL), and K2CO3 (0.83 g, 6 mmol)
and a solution of 2-bromobenzyl bromide (1.25 g, 5 mmol) in
DMF (1 mL) were added subsequently. The mixture was
stirred for 3.5 h at 60 °C, cooled to ambient temperature, and
then filtered through a silica gel plug and washed with ether.
The organic layer was submitted to an aqueous workup (water,
3× ether, brine), dried over MgSO4, and concentrated. The
crude product was purified by flash column chromatography
(ether/hexanes 1:20) yielding 6 as a highly viscous yellow oil
(0.97 g, 2.58 mmol, 52%) that solidified upon storage. Mp: 44
C
21H26BrNO4: C, 57.80; H, 6.01. Found: C, 57.93; H, 6.07.
1
5,6-Dim et h oxy-2-p h en yl-2,3-d ih yd r o-1H -isoin d ole-1-
°C. H NMR (C6D6, 400 MHz) δ: 7.39-7.36 (dd, 1H, J ) 1.1,
ca r boxylic Acid ter t-Bu tyl Ester (9) (Ta ble 1, En tr y 2).
Following the general procedure, 8 (0.218 g, 0.5 mmol) in
dioxane (2.5 mL) was allowed to react for 4 h at 85 °C using
ligand 2. Flash column chromatography (ether/dichloromethane/
hexanes 10:1:1) yielded 9 as pale yellow crystals (0.158 g, 0.445
mmol, 78.6%). Mp: 130 °C. 1H NMR (C6D6, 400 MHz) δ: 7.36-
7.30 (m, 2H), 7.00 (s, 1H), 6.88-6.83 (m, 1H), 6.78-6.73 (m,
2H), 6.41 (s, 1H), 5.41-5.39 (d, 1H, J ) 3.8 Hz), 4.65-4.58
(dd, 1H, J ) 3.8, 12.2 Hz), 4.35-4.30 (d, 1H, J ) 12.2 Hz),
3.41 (s, 3H), 3.37 (s, 3H), 1.24 (s, 9H). 13C NMR (C6D6, 100
MHz) δ: 171.7, 151.2, 150.5, 147.1, 130.8, 130.1, 129.4, 117.7,
112.7, 107.0, 106.7, 81.4, 68.5, 56.1, 56.0, 54.5, 28.2 ppm. IR
(CH2Cl2, cm-1) ν: 3064, 2979, 2939, 2836, 1740, 1600, 1505,
7.95 Hz), 7.28-7.24 (m, 1H), 7.10-7.04 (m, 2H), 6.90-6.85 (dt,
1H, J ) 1.1, 7.6 Hz), 6.73-6.67 (m, 2H), 6.60-6.56 (m, 2H),
4.55 (s, 2H), 3.61 (s, 2H), 1.30 (s, 9H). 13C NMR (C6D6, 100
MHz) δ: 170.3, 149.0, 138.1, 133.3, 129.9, 129.2, 129.1, 128.3,
123.3, 118.4, 113.1, 81.4, 57.9, 54.2, 28.4 ppm. IR (neat, cm-1
)
ν: 3062, 2975, 2930, 2867, 1743, 1600, 1505, 1441, 1391, 1368,
1349, 1260, 1220, 1151, 1025, 990, 964, 846, 748, 690. Anal.
Calcd for C19H22BrNO2: C, 60.65; H, 5.89. Found: C, 60.80;
H, 6.03.
(73) Skiles, J . W.; Suh, J . T.; Williams, B. E.; Menard, P. R.; Barton,
J . N.; Loev, B.; J ones, H.; Neiss, E. S.; A., S.; Mann, W. S.; Khandwala,
A.; Wolf, P. S.; Weinryb, I. J . Med. Chem. 1986, 29, 784.

R-Arylation of R-Amino Acid Esters
J . Org. Chem., Vol. 67, No. 2, 2002 471
1468, 1368, 1333, 1277, 1221, 1148, 1104, 1036, 997, 864, 852,
690. Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09. Found: C,
70.90; H, 7.21.
1.65, 7.7 Hz), 6.82-6.76 (dt, 1H, J ) 1.65, 7.7 Hz), 3.94-3.88
(d, 1H, J ) 14.2 Hz), 3.78-3.72 (d, 1H, J ) 14.2 Hz), 2.93-
2.88 (d, 1H, J ) 6.1 Hz), 1.97-1.83 (m, 2H), 1.38 (s, 9H), 1.00-
0.94 (m, 6H). 13C NMR (C6D6, 100 MHz) δ: 174.5, 140.3, 133.0,
130.5, 128.7, 127.5, 124.6, 80.5, 67.8, 52.7, 32.4, 28.3, 19.9, 18.8
ppm. IR (neat, cm-1) ν: 3340, 3068, 2968, 2933, 2873, 1723,
1569, 1465, 1391, 1368, 1250, 1210, 1144, 1027, 978, 847, 802,
748. Anal. Calcd for C16H24BrNO2: C, 56.15; H, 7.07. Found:
C, 56.32; H, 7.17.
2-(Am in op h en yl)p r op ion ic Acid ter t-Bu tyl Ester . A
round-bottomed flask was charged with aniline (1.86 mL, 20
mmol), 2-bromopropionic acid tert-butyl ester (4.18 g, 20
mmol), NaOAc (1.64 g, 20 mmol), and dry ethanol (1 mL),
purged with argon, and stirred for 11 h at 80 °C. After the
mixture was cooled to room temperature, water and ether were
added, the aqueous layer was extracted three times with ether,
and the combined organic layers were washed with aqueous
sodium bicarbonate and brine and dried over MgSO4. The
solvent was removed, and the crude product was purified by
flash column chromatography (ether/hexanes 1:4) yielding the
title compound as an orange oil (3.47 g, 15.68 mmol, 78%). 1H
NMR (C6D6, 400 MHz) δ: 7.15-6.09 (m, 2H), 6.76-6.72 (m,
1H), 6.51-6.46 (m, 2H), 4.08 (bs, 1H), 3.94-3.88 (q, 1H, J )
6.85 Hz), 1.27 (s, 9H), 1.18 (d, 1H, J ) 6.85 Hz). 13C NMR
(C6D6, 100 MHz) δ: 174.2, 147.8, 129.9, 118.63, 114.2, 81.2,
53.0, 28.3, 19.2 ppm. IR (neat, cm-1) ν: 3348, 2979, 1748, 1478,
1461, 1370, 1235, 1152, 1119, 1073, 841, 752, 719. Anal. Calcd
for C13H19NO2: C, 70.56; H, 8.65. Found: C, 70.52; H, 8.58.
N-(2-Br om oben zyl)-N-p h en ylp r op ion ic Acid ter t-Bu tyl
Ester (10). 2-(Aminophenyl)propionic acid tert-butyl ester
(1.77 g, 8 mmol) was dissolved in DMF (12 mL), followed by
addition of K2CO3 (1.66 g, 12 mmol) and a solution of
2-bromobenzyl bromide (2.49 g, 10 mmol) in DMF (4 mL). The
reaction mixture was stirred for 36 h at 60 °C, with subsequent
addition of 2-bromobenzyl bromide (0.8 g, 3.2 mmol) three
times during the course of reaction. After being cooled to room
temperature, the mixture was filtered through a silica gel plug
and washed with ether. The organic layer was submitted to
an aqueous workup (water, 3× ether, brine), dried over MgSO4,
and concentrated. The crude product was purified by flash
column chromatography (ether/hexanes 1:15) yielding 10 as
a colorless oil (1.28 g, 3.3 mmol, 47%) that solidified upon
storage. Mp: 65 °C. 1H NMR (C6D6, 400 MHz) δ: 7.7.40-7.37
(dd, 1H, J ) 1.1, 7.9 Hz), 7.37-7.33 (dd, 1H, J ) 1.2, 7.7 Hz),
7.10-7.04 (m, 2H), 6.92-6.87 (dt, 1H, J ) 1.0, 7.6 Hz) 6.75-
6.66 (m, 4 H), 4.72-4.78 (d, 1H, J ) 18.7 Hz), 4.66-4.60 (d,
1H, J ) 18.7 Hz), 4.29-4.22 (q, 1H, J ) 7.15 Hz), 1.27 (s, 9H),
1.22-1.25 (d, 3H, J ) 7.15 Hz). 13C NMR (C6D6, 100 MHz) δ:
172.9, 149.6, 139.6, 133.1, 129.9, 129.6, 128.9, 128.1, 122.8,
N-(2-Br om ob en zyl)-N-m et h ylva lin e ter t-Bu t yl E st er
(12). To a stirred solution of N-(2-bromobenzyl)valine tert-butyl
ester (1.6 g, 4.67 mmol) in DMSO (10 mL) was added K2CO3
(0.8 g, 6.1 mmol), followed by MeI (0.35 mL, 5.6 mmol). The
slurry was stirred for 18 h at ambient temperature and then
filtered through silica gel and washed with ether. The organic
layer was submitted to an aqueous workup (water, 3× ether,
brine), dried over MgSO4, and concentrated. The crude product
was purified by flash column chromatography (ether/hexanes
1
1:15) yielding 12 as a colorless oil (1.5 g, 4.2 mmol, 90%). H
NMR (C6D6, 400 MHz) δ: 7.51-7.47 (m, 1H), 7.43-7.39 (dd,
1H, J ) 1.15, 7.85 Hz), 7.03-6.97 (dt, 1H, J ) 1.15, 7.55 Hz),
6.75-6.70 (dt, 1H, J ) 1.75, 7.9 Hz), 3.88 (s, 2H), 2.81-2.77
(d, 1H, J ) 10.8 Hz), 2.29 (s, 3H), 2.13-1.99 (m, 1H), 1.45 (s,
9H), 0.98-0.94 (d, 3H, J ) 6.6 Hz), 0.93-0.87 (d, 3H, J ) 6.55
Hz). 13C NMR (C6D6, 100 MHz) δ: 171.1, 139.5, 133.4, 130.8,
128.6, 127.7, 125.2, 80.6, 74.5, 59.2, 38.0, 28.8, 28.2, 20.4, 20.0
ppm. IR (neat, cm-1) ν: 3064, 2975, 2966, 2873, 2802, 1721,
1466, 1441, 1366, 1250, 1144, 1121, 1025, 980, 912, 862, 835,
796, 750. Anal. Calcd for C17H26BrNO2: C, 57.31; H, 7.36.
Found: C, 57.55; H, 7.18.
1-Isop r op yl-2-m eth yl-2,3-d ih yd r o-1H-isoin d ole-1-ca r -
boxylic Acid ter t-Bu tyl Ester (13) (Ta ble 1, En tr y 5).
Following a modification of the general procedure, 12 (0.178
g, 0.5 mmol) in dioxane (2.5 mL) was allowed to react for 48 h
at 110 °C using Pd2(dba)3 (0.016 g, 7 mol %) and ligand 3
(0.0146 g, 7.5 mol %). Flash column chromatography (ether/
hexanes 1:25) yielded 13 as a colorless oil (0.07 g, 0.26 mmol,
1
51%). H NMR (C6D6, 400 MHz) δ: 7.31-7.25 (m, 1H), 7.16-
7.09 (m, 1H), 7.09-7.00 (m, 2H), 6.98-6.94 (m, 1H), 2.89-
2.77 (m, 1H), 2.76 (s, 3H), 1.25 (s, 9H), 1.08-1.12 (d, 3H, J )
6.95 Hz), 0.98-0.94 (d, 3H, J ) 6.8 Hz). 13C NMR (C6D6, 100
MHz) δ: 172.5, 143.7, 141.5, 127.9, 127.0, 123.8, 122.5, 80.5,
61.7, 38.2, 34.2, 28.6, 28.4, 19.4, 18.3 ppm. IR (neat, cm-1) ν:
2973, 2935, 2875, 2796, 1706, 1466, 1368, 1246, 1160, 1127,
1036, 974, 845, 758, 737, 692. Anal. Calcd for C77H25NO2: C,
74.14; H, 9.15. Found: C, 74.79; H, 9.04.
118.7, 114.2, 81.3, 58.4, 54.2, 28.3, 16.0 ppm. IR (CH2Cl2, cm-1
)
ν: 2979, 2935, 1727, 1600, 1505, 1461, 1441, 1368, 1248, 1148,
1027, 914, 876, 847, 752, 690. Anal. Calcd for C20H24BrNO2:
C, 61.54; H, 6.20. Found: C, 61.80; H, 6.19.
2-[N-(2-Br om oben zyl)]a m in op h en yla cetic Acid ter t-
Bu tyl Ester . To a stirred solution of 2-aminophenylacetic tert-
butyl ester (1.04 g, 5.0 mmol) in DMF (7 mL) was added K2CO3
(1.04 g, 7.5 mmol), followed by a solution of 2-bromobenzyl
bromide (1.5 g, 6 mmol) in DMF (3 mL). The slurry was stirred
for 4 h at ambient temperature and then filtered through silica
gel and washed with ether. The organic layer was submitted
to an aqueous workup (water, 3× ether, brine), dried over
MgSO4, and concentrated. The crude product was purified by
flash column chromatography (ether/hexanes 1:10) yielding the
2-P h en yl-1-m eth yl-2,3-d ih yd r o-1H-isoin d ole-1-ca r box-
ylic Acid ter t-Bu tyl Ester (11) (Ta ble 1, En tr y 3). Follow-
ing the general procedure, 10 (0.195 g, 0.5 mmol) in dioxane
(2.5 mL) was allowed to react for 24 h at 85 °C using ligand 2.
Flash column chromatography (ether/hexanes 1:20) yielded 11
as a pale yellow oil (0.142 g, 0.46 mmol, 92%). 1H NMR (C6D6,
400 MHz) δ: 7.29-7.21 (m, 3H), 7.08-7.02 (m, 2H), 7.01-
6.97 (m, 1H), 6.83-6.76 (m, 3H), 4.57-4.52 (d, 1H, J ) 12.95
Hz), 4.52-4.46 (d, 1H, J ) 12.95 Hz), 1.99 (s, 3H), 1.08 (s,
9H). 13C NMR (C6D6, 100 MHz) δ:_173.4, 146.4, 144.9, 137.5,
129.7, 128.5, 128.1, 123.0, 122.0, 117.6, 114.0, 81.1, 73.0, 55.8,
27.8, 23.4 ppm. IR (neat, cm-1) ν: 3043, 2944, 2939, 2871, 2833,
1723, 1602, 1505, 1463, 1356, 1343, 1245, 1160, 1117, 991, 908,
845, 746, 692. Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49.
Found: C, 77.44; H, 7.52.
N-(2-Br om oben zyl)va lin e ter t-Bu tyl Ester . To a stirred
solution of valine tert-butyl ester (1 g, 5.77 mmol) in DMF (8
mL) was added K2CO3 (1.04 g, 7.5 mmol), followed by a solution
of 2-bromobenzyl bromide (1.44 g, 5.8 mmol) in DMF (4 mL).
The slurry was stirred for 2 h at 80 °C and then, after being
cooled to room temperature, filtered through silica gel and
washed with ether. The organic layer was submitted to an
aqueous workup (water, 3× ether, brine), dried over MgSO4,
and concentrated. The crude product was purified by flash
column chromatography (ether/hexanes 1:7) yielding the title
compound as a colorless oil (1.66 g, 4.84 mmol, 83%). 1H NMR
(C6D6, 400 MHz) δ: 7.43-7.38 (dd, 1H, J ) 1.45, 7.45 Hz),
7.37-7.33 (dd, 1H, J ) 1.0, 7.95 Hz), 6.97-6.91 (dt, 1H, J )
1
title compound as a colorless oil (1.83 g, 4.86 mmol, 97%). H
NMR (C6D6, 400 MHz) δ: 7.47-7.43 (m, 2H), 7.39-7.35 (dd,
1H, J ) 1.6, 7.75 Hz), 7.35-7.31 (dd, 1H, J ) 1.15, 7.9 Hz),
7.18-7.12 (m, 2H), 7.10-7.04 (m, 1H), 6.93-6.88 (dt, 1H, J )
1.15, 7.55 Hz), 6.70-6.64 (dt, 1H, J ) 1.7, 7.7 Hz), 4.33 (s,
1H), 3.80 (s, 2H), 2.54 (s, 1H), 1.24 (s, 9H). 13C NMR (C6D6,
100 MHz) δ: 172.4, 140.0, 139.8, 133.2, 130.7, 129.1, 129.0,
128.3, 128.2, 127.9, 124.7, 81.3, 66.0, 51.7, 28.2 ppm. IR (neat,
cm-1) ν: 3346, 3064, 3029, 2979, 2933, 1727, 1569, 1455, 1393,
1368, 1248, 1148, 1025, 947, 845, 748, 696. Anal. Calcd for
C
19H22BrNO2: C, 60.65; H, 5.89. Found: C, 60.55; H, 5.82.
N-(2-Br om oben zyl)-N-m eth ylp h en ylglycin e ter t-Bu tyl
Ester (14). To a stirred solution of N-(2-bromobenzyl) phen-
ylglycine tert-butyl ester (1.43 g, 3.8 mmol) in DMSO (8 mL)
was added K2CO3 (078 g, 5.7 mmol), followed by MeI (0.32 mL,
5.1 mmol). The slurry was stirred for 18 h at ambient
temperature and then filtered through silica gel and washed
with ether. The organic layer was submitted to an aqueous
workup (water, 3× ether, brine), dried over MgSO4, and

472 J . Org. Chem., Vol. 67, No. 2, 2002
Gaertzen and Buchwald
concentrated. The crude product was purified by flash column
chromatography (ether/hexanes 1:20) yielding 14 as a colorless
oil (1.01 g, 2.6 mmol, 68%). 1H NMR (C6D6, 400 MHz) δ: 7.73-
7.68 (dd, 1H, J ) 1.5, 7.7 Hz), 7.60-7.56 (m, 2H), 7.38-7.34
(dd, 1H, J ) 1.1, 8.0 Hz), 7.16-7.10 (m, 2H), 7.07-7.03 (m,
1H), 7.03-6.98 (dt, 1H, J ) 1.1, 7.6 Hz), 6.73-667 (dt, 1H, J
) 1.7, 7.7 Hz), 4.40 (s, 1H), 3.99-3.93 (d, 1H, J ) 14.65 Hz),
to an aqueous workup (water, 3× ether, brine), dried over
MgSO4, and concentrated. The crude product was purified by
flash column chromatography (ether/hexanes 1:15) yielding 18
as a colorless oil (0.92 g, 2.59 mmol, 47%). 1H NMR (C6D6, 400
MHz) δ: 7.71-7.67 (dd, 1H, J ) 1.1, 7.5 Hz), 7.42-7.38 (dd,
1H, J ) 1.1, 8.0 Hz), 7.04-6.98 (dt, 1H, J ) 1.0, 7.5 Hz), 6.75-
6.68 (dt, 1H, J ) 1.45, 7.5 Hz), 4.04-3.98 (d, 1H, J ) 14.85
Hz), 3.82-3.75 (d, 1H, J ) 14.85 Hz), 3.30-3.23 (m, 1H) 3.05-
2.97 (ddd, 1H, J ) 3.5, 8.15, 11.4 Hz), 2.26-217 (ddd, 1H, J )
4.05, 6.15, 10.7 Hz), 1.96-1.87 (m, 1H), 1.78-1.70 (m, 1H),
1.49-1.19 (m, 4H), 1.36 (s, 9H). 13C NMR (C6D6, 100 MHz) δ:
173.1, 139.7, 133.2, 131.4, 128.8, 127.8, 125.1, 80.4, 64.8, 60.4,
49.7, 30.1, 28.5, 26.3, 22.6 ppm. IR (neat, cm-1) ν: 3061, 2975,
2934, 2855, 1726, 1566, 1440, 1366, 1149, 1025, 1002, 848, 751.
High resolution MS: calcd [M + H] 354.1063, found 354.1059.
Anal. Calcd for C17H24BrNO2: C, 57.63; H, 6.83. Found: C,
58.05; H, 6.93.
3.88-3.83 (d, 1H, J ) 14.65 Hz), 2.25 (s, 3H), 1.32 (s, 9H). 13
C
NMR (C6D6, 100 MHz) δ: 171.1, 139.3, 138.1, 133.0, 131.1,
129.3, 128.8, 128.5, 128.3, 127.7, 124.8, 81.0, 73.4, 58.5, 39.0,
28.2 ppm. IR (neat, cm-1) ν: 3064, 2977, 2933, 2850, 2798,
1729, 1567, 1453, 1368, 1254, 1219, 1140, 1025, 945, 837, 795,
748, 698. Anal. Calcd for C20H24BrNO2: C, 61.54; H, 6.20.
Found: C, 61.80; H, 6.14.
1-P h en yl-2-m eth yl-2,3-d ih yd r o-1H-isoin d ole-1-ca r box-
ylic Acid ter t-Bu tyl Ester (15) (Ta ble 1, En tr y 6). Follow-
ing the general procedure, 14 (0.195 g, 0.5 mmol) in dioxane
(2.5 mL) was allowed to react for 2 h at 90 °C using ligand 3.
Flash column chromatography (ether/hexanes 1:12) yielded 15
as an orange oil (0.151 g, 0.49 mmol, 99%). 1H NMR (C6D6,
400 MHz) δ: 7.53-7.49 (m, 2H), 7.39-7.35 (m, 1H), 7.21-
7.15 (m, 1H), 7.12-7.01 (m, 5H), 4.23-4.18 (d, 1H, J ) 12.25
Hz), 4.15-4.00 (d, 1H, J ) 12.25 Hz), 2.60 (s, 3 H), 1.24 (s,
9H). 13C NMR (C6D6, 100 MHz) δ: 171.3, 145.2, 141.6, 141.5,
129.2, 128.5, 128.1, 127.8, 127.4, 125.3, 122.5, 81.3, 80.6, 59.0,
35.4, 28.4 ppm. IR (neat, cm-1) ν: 3029, 2977, 2873, 2792, 1723,
1600, 1476, 1461, 1368, 1241, 1150, 1030, 972, 843, 766, 750,
733, 698. Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49.
Found: C, 77.84; H, 7.35.
1-(2-Br om oben zyl)p yr r olid in e-2-ca r boxylic Acid ter t-
Bu tyl Ester (16). To a stirred solution of proline tert-butyl
ester (1 g, 5.84 mmol) in DMF (8 mL) was added K2CO3 (1.24
g, 9 mmol), followed by a solution of 2-bromobenzyl bromide
(1.5 g, 6 mmol) in DMF (4 mL). The slurry was stirred for 15
h at ambient temperature and then filtered through silica gel
and washed with ether. The organic layer was submitted to
an aqueous workup (water, 3× ether, brine), dried over MgSO4,
and concentrated. The crude product was purified by flash
column chromatography (ether/hexanes 1:10) yielding 16 as
a colorless oil (1.65 g, 4.84 mmol, 83%). 1H NMR (C6D6, 400
MHz) δ: 7.70-7.66 (dd, 1H, J ) 1.1, 7.7 Hz), 7.41-7.37 (dd,
1 H, J ) 1.25, 7.6 Hz), 7.04-6.98 (dt, 1H, J ) 1.7, 7.6 Hz),
6.75-6.68 (dt, 1H, J ) 1.7, 7.8 Hz), 4.16-4.10 (d, 1 H, J )
14.55 Hz), 3.91-3.86 (d, 1H, J ) 14.55 Hz), 3.32-3.27 (dd,
1H, J ) 5.2, 8.6 Hz), 2.98-2.91 (ddd, 1H, J ) 4.0, 8.3, 12.6
Hz), 2.34-2.26 (dt, 1H, J ) 7.6, 8.6 Hz), 2.00-1.91 (m, 1 H),
1.88-1.78 (m, 1H), 1.78-1.66 (m, 1H), 1.51-1.38 (m, 1H), 1.34
(s, 9H). 13C NMR (C6D6, 100 MHz) δ: 173.3, 139.8, 133.1, 131.4,
128.8, 127.8, 124.6, 80.3, 66.6, 58.0, 53.4, 29.7, 28.4, 24.1 ppm.
IR (neat, cm-1) ν: 3061, 2975, 2833, 1725, 1567, 1439, 1367,
1,2,3,4-Tetr a h yd r o-6H-p yr id o[2,1-a ]-isoin d ole-10b-ca r -
boxylic Acid ter t-Bu t yl E st er (19) (Ta ble 1, E n t r y 12).
Following the general procedure, 18 (0.177 g, 0.5 mmol) in
dioxane (2.5 mL) was allowed to react for 20 h at 85 °C using
ligand 2. Flash column chromatography (ether/hexanes 1:6)
1
yields 19 as a yellow oil (0.115 g, 0.42 mmol, 84%). H NMR
(C6D6, 400 MHz) δ: 7.44-7.39 (m, 1H), 7.11-699 (m, 3H),
4.43-4.36 (d, 1H, J ) 11.65 Hz), 4.01-3.95 (d, 1H, J ) 11.65
Hz), 3.46-3.37 (m, 1H), 2.93-2.87 (m, 1H), 2.75-2.68 (m, 1H),
1.69-1.48 (m, 4H), 1.43-1.35 (m, 1H), 1.25 (s, 9H). 13C NMR
(C6D6, 100 MHz) δ:_173.1, 145.5, 141.5, 127.9, 127.1, 132.2,
122.3, 80.6, 73.0, 56.5, 45.8, 33.2, 28.4, 24.6, 22.9 ppm. IR (neat,
cm-1) ν: 2973, 2931, 2854, 2811, 1720, 1611, 1473, 1459, 1391,
1367, 1343, 1289, 1245, 1164, 1139, 1093, 1009, 954, 893, 844,
758, 735, 659. High resolution MS: calcd for [C17H23NO2
H] 274.1802, found 274.1811.
+
2-Br om o-N-p h en ylp h en eth yla m in e.74,75 To a stirred so-
lution of KO-t-Bu (1.12 g, 10 mmol) in DMSO (30 mL) was
added dropwise aniline (1.08 mL, 12 mmol), followed by slow
addition of 2-bromostyrene (1.29 mL, 10 mmol). The mixture
was stirred for 15 h at 40 °C, cooled to 0 °C, and quenched
with water. Ether was added, the aqueous layer was neutral-
ized (pH ) 7) with 4 N H2SO4 and extracted three times with
ether, and the combined organic layers were dried over MgSO4.
After evaporation of the solvent, the crude product was further
purified by flash column chromatography (ether/hexanes 1:15)
to yield the title compound as an orange oil (2.18 g, 7.9 mmol,
79%). 1H NMR (C6D6, 400 MHz) δ: 7.39-7.35 (dd, 1H, J )
1.0, 7.95 Hz), 7.21-7.14 (m, 2H), 6.87-6.73 (m, 3H), 6.69-
6.63 (dt, 1H, J ) 2.0, 7.9 Hz), 6.47-6.41 (m, 2H), 3.12-3.06
(m, 3H), 2.75-2.69 (m, 2H). 13C NMR (C6D6, 100 MHz) δ:
148.62, 139.67, 133.5, 131.6, 130.0, 128.0, 125.3, 118.0, 113.7,
113.5, 43.7, 36.3 ppm. IR (neat, cm-1) ν: 3392, 3053, 2979,
2935, 2877, 1727, 1603, 1507, 1455, 1368, 1316, 1256, 1219,
1146, 1050, 849, 746, 692. Anal. Calcd for C14H14BrN: C, 60.89;
H, 5.11. Found: C, 61.07; H, 5.06.
1255, 1213, 1153, 1025, 845, 752, 660. Anal. Calcd for C16H22
BrNO2: C, 56.48; H, 6.52. Found: C, 56.27; H, 6.40.
-
2,3-Dih yd r o-1H,5H-p yr r olo[2,1-a ]isoin d ole-9b-ca r box-
ylic Acid ter t-Bu tyl Ester (17) (Ta ble 1, En tr y 10).
Following the general procedure, 16 (017 g, 0.5 mmol) in
dioxane (2.5 mL) was allowed to react for 20 h at 85 °C using
ligand 2. Flash column chromatography (ether/hexanes) yielded
17 as a yellow oil (0.08 g, 0.31 mmol, 62%). 1H NMR (C6D6,
400 MHz) δ: 7.36-7.33 (m, 1H), 7.13-7.04 (m, 2H), 6.96-
6.92 (m, 1H), 4.59-4.52 (d, 1H, J ) 14.85 Hz), 3.66-3.58 (d,
1H, J ) 14.85 Hz), 3.25-3.18 (m, 1H), 2.91-2.81 (m, 1H),
2.36-2.88 (m, 1H), 1.86-1.73 (m, 2H), 1.48-1.37 (m, 1H), 1.28
(s, 9H). 13C NMR (C6D6, 100 MHz) δ: 173.9, 145.0, 141.6, 129.1,
127.8, 123.8, 123.2, 83.1, 80.3, 60.9, 57.7, 36.5, 28.2, 26.6 ppm.
IR (neat, cm-1) ν: 3072, 2971, 2931, 2865, 2809, 1721, 1457,
1366, 1283, 1252, 1237, 1154, 1111, 1086, 1055, 986, 935, 847,
762, 737, 718, 685. Anal. Calcd for C16H21NO2: C, 74.10; H,
8.16. Found: C, 74.17; H, 8.24.
1-(2-Br om oben zyl)p ip er id in e-2-ca r b oxylic Acid ter t-
Bu tyl Ester (18). To a stirred solution of tert-butyl pipecoli-
nate (1 g, 5.5 mmol) in DMF (8 mL) was added K2CO3 (1.14 g,
8.25 mmol), followed by a solution of 2-bromobenzyl bromide
(1.37 g, 5.5 mmol) in DMF (4 mL). The slurry was stirred for
8 h at ambient temperature and then filtered through silica
gel and washed with ether. The organic layer was submitted
2-[[2-(2-Br om op h en yl)eth yl]p h en yla m in o]a cetic Acid
ter t-Bu tyl Ester (20). A round-bottomed flask was charged
with 2-bromo-N-(phenyl)phenethylamine (2.18 g, 7.9 mmol),
2-bromoacetic acid tert-butyl ester (1.17 mL, 7.9 mmol), NaOAc
(0.65 g, 7.9 mmol), and dry ethanol (0.5 mL), purged with
argon, and stirred for 5 h at 75 °C. After the mixture was
cooled to room temperature, water and ether were added, the
aqueous layer was extracted three times with ether, and the
combined organic layers were washed with aqueous sodium
bicarbonate and brine and dried over MgSO4. To remove
residual amine (not separable by chromatography), the crude
product was dissolved in dichloromethane (16 mL) and treated
with acetyl chloride (0.14 mL, 2 mmol) and triethylamine (0.34
mL, 2.4 mmol). The mixture was stirred for 1 h at ambient
temperature and submitted to aqueous workup (water, 3×
ether, brine). The organic layer was dried over MgSO4 and
concentrated, and the crude product was purified by flash
(74) Rodriguez, A. L.; Bunlaksananusorn, T.; Knochel, P. Org. Lett.
2000, 2, 3285.
(75) Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J . Org.
Chem. 2001, 66, 1403.

R-Arylation of R-Amino Acid Esters
J . Org. Chem., Vol. 67, No. 2, 2002 473
column chromatography (ether/hexanes 1:5) yielding 20 as an
orange oil (2.59 g, 6.64 mmol, 84%). 1H NMR (C6D6, 400 MHz)
δ: 7.35-7.31 (d, 1H, J ) 7.8 Hz), 7.26-7.21 (m, 2H), 6.84-
6.74 (m, 5H), 6.68-6.61 (m, 1H), 3.72 (s, 2H), 3.57-3.50 (m,
2H), 3.02-2.95 (m, 2H), 1.27 (s, 9H). 13C NMR (C6D6, 100 MHz)
δ:_170.4, 148.5, 139.6, 133.4, 131.7, 130.0, 129.0, 125.2, 117.7,
112.7, 81.2, 54.5, 52.8, 35.0, 28.3 ppm. IR (neat, cm-1) ν: 3060,
2976, 2931, 1743, 1599, 1506, 1470, 1391, 1367, 1255, 1219,
1150, 1022, 848, 746, 691, 659. High resolution MS: calcd for
mixture was cooled to room temperature, water and ether were
added, the aqueous layer was extracted three times with ether,
and the combined organic layers were washed with aqueous
sodium bicarbonate and brine and dried over MgSO4. To
remove residual amine (not separable by chromatography), the
crude product was dissolved in dichloromethane (10 mL) and
treated with acetyl chloride (0.27 mL, 3.75 mmol) and triethyl-
amine (0.57 mL, 4.06 mmol). The mixture was stirred for 1 h
at ambient temperature and submitted to an aqueous workup
(water, 3× ether, brine). The organic layer was dried over
MgSO4 and concentrated, and the crude product was purified
by flash column chromatography (ether/hexanes 1:20) yielding
C
20H24BrNO2 [M + Na] 412.0883, found 412.0900.
2-P h en yl-1,2,3,4-t et r a h yd r oisoq u in olin e-1-ca r b oxyl-
ic Acid ter t-Bu tyl Ester (21) (Ta ble 2, En tr y 1). Following
the general procedure, 20 (0.197 g, 0.5 mmol) in dioxane (2.5
mL) was allowed to react for 9 h at 85 °C using ligand 3. Flash
column chromatography (ether/hexanes 1:15) yielded 21 as a
colorless oil (0.121 g, 0.39 mmol, 79%). 1H NMR (C6D6, 400
MHz) δ: 7.50-7.46 (m, 1H), 7.29-7.22 (m, 2H), 7.09-7.01 (m,
2H), 6.97-6.87 (m, 3H), 6.86-6.81 (dt, 1H, J ) 0.9, 7.3 Hz),
5.30 (s, 1H), 3.76-3.68 (ddd, 1H, J ) 4.7, 7.4, 11.6 Hz), 3.34-
3.23 (ddd, 1H, J ) 5.1, 6.8, 11.6 Hz), 3.00-2.92 (ddd, 1H, J )
4.85, 6.6, 15.45 Hz), 2.60-2.69 (ddd, 1H, J ) 5.1, 7.25, 15.45
Hz), 1.19 (s, 9H). 13C NMR (C6D6, 100 MHz) δ: 172.3, 150.2,
136.3, 133.2, 129.0, 128.0, 126.8, 118.8, 114.6, 81.4, 63.6, 43.3,
29.6, 28.1 ppm. IR (neat, cm-1) ν: 3062, 3028, 2975, 2927, 2867,
1737, 1599, 1503, 1389, 1367, 1293, 1231, 1144, 1035, 956, 847,
747, 690. Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49.
Found: C, 77.47; H, 7.52.
2-[[2-(2-Br om o-4,5-d im e t h oxyp h e n yl)e t h yl]m e t h yl-
a m in o]a cetic Acid ter t-Bu tyl Ester (22). A round-bot-
tomedflask was charged with 5-bromo-(N-methyl)homovera-
trylamine76 (1.5 g, 5.47 mmol), 2-bromoacetic acid tert-butyl
ester (0.81 mL, 6.02 mmol), NaOAc (0.49 g, 6.02 mmol), and
dry ethanol (0.5 mL), purged with argon, and stirred for 22 h
at 75 °C. After the mixture was cooled to room temperature,
water and ether were added, the aqueous layer was extracted
three times with ether, and the combined organic layers were
washed with aqueous sodium bicarbonate and brine and dried
over MgSO4. After removal of solvent, the crude product was
purified by flash column chromatography (ether/dichlo-
romethane 1:10) yielding 22 as an orange oil (0.83 g, 2.14
mmol, 54%), which solidified upon storage. Mp: 91 °C. 1H
NMR (C6D6, 400 MHz) δ: 6.91 (s, 1H), 6.68 (s, 1H), 3.37 (s,
3H), 3.19 (s, 2H), 3.17 (s, 3H), 2.95-2.82 (m, 4H), 2.42 (s, 3H),
1.37 (s, 9H). 13C NMR (C6D6, 100 MHz) δ: 170.5, 149.9, 149.6,
132.3, 116.7, 114.9, 114.8, 80.4, 59.8, 57.5, 56.0, 53.6, 42.4, 34.9,
28.5 ppm. IR (neat, cm-1) ν: 3055, 2974, 2934, 2840, 2801,
1737, 1603, 1573, 1509, 1463, 1381, 1367, 1257, 1215, 1162,
1036, 962, 853, 799, 735, 602. Anal. Calcd for C17H26BrNO4:
C, 52.58; H, 6.75. Found: C, 52.68; H, 6.71.
1
24 as an orange oil (1.1 g, 2.73 mmol, 44%). H NMR (C6D6,
400 MHz) δ: 7.38-7.34 (dd, 1H, J ) 1.1, 8 Hz), 7.28-7.23 (m
2H), 6.97-6.92 (m, 3H), 6.88-6.78 (m, 2H), 6.68-6.63 (dt, 1H,
J ) 1.7, 7.7 Hz), 4.24-4.16 (q, 1H, J ) 7.2 Hz), 3.67-3.52 (m,
2H), 3.15-3.07 (m, 2H), 1.34-1.31 (d, 1H, J ) 7.2 Hz), 1.25
(s, 9H). 13C NMR (C6D6, 100 MHz) δ:_173.0, 149.1, 140.1, 133.4,
131.7, 129.9, 128.5, 128.1, 125.2, 118.5, 114.9, 80.9, 59.3, 47.9,
36.1, 28.7, 16.4 ppm. IR (neat, cm-1) ν: 3060, 2979, 2935, 2873,
1725, 1600, 1505, 1472, 1368, 1258, 1214, 1146, 1063, 1040,
1027, 930, 849, 746, 692. Anal. Calcd for C21H26BrNO2: C,
62.38; H, 6.48. Found: C, 62.44; H, 6.46.
1-Met h yl-2-p h en yl-1,2,3,4-t et r a h yd r oisoq u in olin e-1-
ca r boxylic Acid ter t-Bu tyl Ester (25) (Ta ble 2, En tr y 3).
Following the general procedure, 24 (0.202 g, 0.5 mmol) in
dioxane (2.5 mL) was allowed to react for 24 h at 85 °C using
ligand 3. Flash column chromatography (ether/hexanes 1:25)
1
yielded 25 as a yellow oil (0.101 g, 0.31 mmol, 62%). H NMR
(C6D6, 400 MHz) δ: 7.44-7.40 (m, 1H), 7.21-7.11 (m, 6H),
7.08-6.97 (m, 2H), 6.96-6.92 (m, 1H), 6.90-6.84 (m, 1H),
3.76-3.68 (ddd, 1H, J ) 4.4, 7.25, 11.8 Hz), 3.21-3.29 (m, 1H),
2.82-2.70 (m, 2H), 1.86 (s, 3H), 1.16 (s, 9H). 13C NMR (C6D6,
100 MHz) δ: 174.3, 150.6, 140.4, 135.6, 129.4, 129.29, 128.3,
127.1, 126.9, 126.6, 81.0, 67.3, 46.9, 31.4, 27.9, 26.2 ppm. IR
(neat, cm-1) ν: 3059, 2976, 2932, 2867, 1723, 1598, 1495, 1451,
1391, 1367, 1251, 1158, 1111, 1062, 1034, 847, 755, 695. Anal.
Calcd for C21H25NO2: C, 77.98; H, 7.79. Found: C, 77.69; H,
7.82.
2-[[2-(2-Br om o-4,5-d im e t h oxyp h e n yl)e t h yl]m e t h yl-
a m in o]p r op ion ic Acid ter t-Bu tyl Ester (26). A round-
bottomed flask was charged with 5-bromo-N-methylhomo-
veratrylamine76 (1.6 g, 5.8 mmol), 2-bromopropionic acid tert-
butyl ester (0.57 g, 6.96 mmol), NaOAc (0.57 g, 6.96 mmol),
and dry ethanol (0.5 mL), purged with argon, and stirred for
41 h at 70 °C. After the mixture was cooled to room temper-
ature, water and ether were added, the aqueous layer was
extracted three times with ether, and the combined organic
layers were washed with aqueous sodium bicarbonate and
brine and dried over MgSO4. After removal of solvent the crude
product was purified by flash column chromatography (gradi-
ent ether/dichloromethane 1:30-1:10) yielding 26 as an orange
6,7-Dim eth oxy-2-m eth yl-1,2,3,4-tetr ah ydr oisoqu in olin e-
1-ca r boxylic Acid ter t-Bu tyl Ester (23) (Ta ble 2, En tr y
2). Following the general procedure, 22 (0.194 g, 0.5 mmol) in
dioxane (2.5 mL) was allowed to react for 3 h at 85 °C using
ligand 3. Flash column chromatography (ether/dichloromethane/
hexanes 3:5:2) yielded 23 as a yellow oil (0.112 g, 0.36 mmol,
1
oil (1.53 g, 3.8 mmol, 66%). H NMR (C6D6, 400 MHz) δ: 6.92
(s, 1H), 6.63 (s, 1H), 3.39-3.32 (q, 1H, J ) 7.1 Hz), 3.34 (s,
3H), 3.19 (s, 3H), 3.07-3.01 (m, 1H), 2.99-2.88 (m, 3H), 2.49
(s, 3H), 1.38 (s, 9H), 1.28-1.24 (d, 2H, J ) 7.1 Hz). 13C NMR
(C6D6, 100 MHz) δ: 172.8, 149.8, 149.6, 132.5, 116.7, 115.0,
114.9, 80.3, 62.8, 56.0, 55.8, 55.3, 38.4, 35.8, 28.6, 16.1; IR
(neat, cm-1) ν: 2975, 2937, 2842, 2807, 1721, 1603, 1509, 1463,
1439, 1383, 1366, 1337, 1256, 1216, 1162, 1146, 1096, 1034,
962, 850, 793 ppm. Anal. Calcd for C18H28BrNO4: C, 53.74;
H, 7.01. Found: C, 53.97; H, 6.89.
1
73%) that solidified upon storage. Mp: 134-136 °C. H NMR
(C6D6, 400 MHz) δ: 6.97 (s, 1H), 6.40 (s, 1H), 4.34 (s, 1H),
3.55-3.46 (m, 1H), 3.50 (s, 3H), 3.37 (s, 3H), 2.81-2.72 (m,
1H), 2.71-2.66 (dt, 1H, J ) 4.8, 15.75 Hz), 2.57-2.49 (m, 1H),
2.53 (s, 3H), 1.35 (s, 9H). 13C NMR (C6D6, 100 MHz) δ: 172.3,
149.7, 148.8, 127.6, 125.3, 113.0, 110.9, 80.8, 68.0, 56.0, 55.8,
48.5, 43.7, 29.3, 28.5 ppm. IR (neat, cm-1) ν: 2972, 2932, 2852,
2804, 1728, 1611, 1518, 1464, 1368, 1324, 1290, 1260, 1225,
1147, 1071, 1016, 982, 938, 851, 815, 784. Anal. Calcd for
6,7-Dim eth oxy-1,2-d im eth yl-1,2,3,4-tetr a h yd r oisoqu in -
olin e-1-ca r boxylic Acid ter t-Bu tyl Ester (27) (Ta ble 2,
En tr y 6). Following the general procedure, 26 (0.203 g, 0.5
mmol) in dioxane (2.5 mL) was allowed to react for 45 h at
100 °C using ligand 3. Flash column chromatography (ether/
hexanes 2:3) yielded 27 as a yellow oil (0.106 g, 0.33 mmol,
C
17H25NO4: C, 66.43; H, 8.20. Found: C, 66.36; H, 8.29.
2-[[2-(2-Br om op h en yl)et h yl]p h en yla m in o]p r op ion ic
Acid ter t-Bu tyl Ester (24). A round-bottomed flask was
charged with 2-bromo-N-(phenyl)phenethylamine (1.73 g, 6.25
mmol), 2-bromopropionic acid tert-butyl ester (2.88 g, 13.75
mmol), NaOAc (0.52 g, 6.25 mmol), and dry ethanol (0.5 mL),
purged with argon, and stirred for 96 h at 75 °C. After the
1
66%). H NMR (C6D6, 400 MHz) δ: 6.98 (s, 1H), 6.38 (s, 1H),
3.47 (s, 3H), 3.37 (s, 3H), 3.36-2.29 (m, 1H), 2.96-2.87 (ddd,
1H, J ) 5.2, 9.35, 14.8 Hz), 2.73-2.67 (dt, 1H, J ) 4.85, 9.3
Hz), 2.64-2.56 (dt, 1H, J ) 4, 15.3 Hz), 2.49 (s, 3H), 1.79 (s,
3H), 1.30 (s, 9H). 13C NMR (C6D6, 100 MHz) δ:_174.2, 149.2,
149.0, 131.5, 127.1, 112.7, 110.5, 80.5, 66.8, 56.1, 55.7, 48.7,
39.9, 30.4, 28.4, 25.2 ppm. IR (neat, cm-1) ν: 2977, 2941, 2908,
(76) Rodr´ıguez, G.; Castedo, L.; Dom´ınguez, D.; Saa´, C.; Adam, W.
J . Org. Chem. 1999, 64, 4830.

474 J . Org. Chem., Vol. 67, No. 2, 2002
Gaertzen and Buchwald
2834, 2804, 1717, 1613, 1515, 1465, 1451, 1368, 1329, 1254,
1221, 1162, 1106, 1067, 1027, 1001, 847, 793, 744, 704. Anal.
Calcd for C18H27NO4: C, 67.26; H, 8.47. Found: C, 67.50; H,
8.64.
ligand 3. Flash column chromatography (ether/hexanes 1:5)
yielded 31 as a yellow oil (0.117 g, 0.406 mmol, 81%). 1H NMR
(C6D6, 400 MHz) δ: 7.68-7.64 (dd, 1H, J ) 1.1, 7.8 Hz), 7.13-
7.07 (dt, 1H, J ) 1.1, 7.8 Hz), 7.06-7.01 (dt, 1H, J ) 1.3, 7.4
Hz), 6.96-6.92 (dd, 1H, J ) 1.3, 7.4 Hz), 4.02-3.93 (dt, 1H, J
) 3.9, 11.3 Hz), 3.26-3.17 (dt, 1H, J ) 2.8, 11.7 Hz), 3.13-
3.03 (ddd, 1H, J ) 6.5, 11.2, 15.8 Hz), 2.83-2.77 (m, 1H), 2.75-
2.69 (m, 1H), 2.69-2.63 (ddd, 1H, J ) 1.9, 6.5, 11.7 Hz), 2.56-
2.49 (ddd, 1H, J ) 1.7, 3.6, 15.8 Hz), 1.77-1.56 (m, 4H), 1.50-
1.42 (m, 1H), 1.27 (s, 9H). 13C NMR (C6D6, 100 MHz) δ: 173.4,
139.0, 136.2, 130.2, 127.4, 127.2, 126.4, 81.0, 67.2, 52.9, 49.0,
38.1, 31.1, 28.6, 26.7, 24.1 ppm. IR (neat, cm-1) ν: 2975, 2931,
2861, 1717, 1453, 1391, 1368, 1302, 1237, 1158, 1144, 1123,
1081, 1054, 1015, 959, 849, 839, 791, 754, 731. Anal. Calcd
for C18H25NO2: C, 75.22; H, 8.77. Found: C, 75.00; H, 8.81.
2-(2-Br om oben zyl)a m in op r op ion ic Acid ter t-Bu tyl Es-
ter . To a stirred solution of alanine tert-butyl ester hydrochlo-
ride (1.09 g, 6.0 mmol) in DMF (8 mL) was added K2CO3 (2.07
g, 15 mmol), followed by a solution of 2-bromobenzyl bromide
(1.5 g, 6 mmol) in DMF (4 mL). The slurry was stirred for 4 h
at ambient temperature and then filtered through silica gel
and washed with ether. The organic layer was submitted to
an aqueous workup (water, 3× ether, brine), dried over MgSO4,
and concentrated. The crude product was purified by flash
column chromatography (ether/hexanes 1:5) yielding the title
1-[2-(2-Br om op h en yl)et h yl]p yr r olid in e-2-ca r b oxylic
Acid ter t-Bu tyl Ester (28). To a stirred solution of proline
tert-butyl ester (1.0 g, 5.84 mmol) in DMF (4 mL) and toluene
(2 mL) was added K2CO3 (1.24 g, 9 mmol), followed by a
solution of 2-bromophenethyl bromide (1.69 g, 6.42 mmol) in
DMF (2 mL). The slurry was stirred for 20 h at 80 °C, at which
point monitoring by GC showed that little conversion had
occurred. DBU (0.88 mL, 5.84 mmol) was added, and the
mixture was stirred for an additional 7 h at 80 °C and then
filtered through a silica gel plug and washed with ether. The
organic layer was submitted to an aqueous workup (water, 3×
ether, brine), dried over MgSO4, and concentrated. The crude
product was purified by flash column chromatography (gradi-
ent ether/hexanes 1:10-1:3) yielding 28 as a colorless oil (1.4
1
g, 3.95 mmol, 68%). H NMR (C6D6, 400 MHz) δ: 7.40-7.36
(dd, 1H, J ) 1.1, 7.6 Hz), 7.13-7.09 (dd, 1H, J ) 1.6, 7.5 Hz),
6.93-6.86 (dt, 1H, J ) 1.1, 7.5 Hz), 6.69-6.62 (dt, 1H, J )
1.7, 7.6 Hz), 3.19-2.94 (m, 5H), 2.73-2.64 (m, 1H), 2.33-2.25
(m, 1H), 2.00-1.88 (m, 1H), 1.86-1.81 (m, 2H), 1.54-1.42 (m,
1H), 1.36 (s, 9H). 13C NMR (C6D6, 100 MHz) δ: 173.5, 140.7,
133.3, 131.5, 128.3, 127.9, 125.3, 80.1, 66.9, 54.7, 53.5, 36.2,
29.7, 28.5, 24.1 ppm. IR (neat, cm-1) ν: 2973, 2875, 2806, 1723,
1472, 1391, 1366, 1256, 1212, 1150, 1111, 1030, 978, 939, 911,
847, 748. Anal. Calcd for C17H24BrNO2: C, 57.63; H, 7.83.
Found: C, 57.77; H, 6.80.
1
compound as a colorless oil (1.38 g, 4.4 mmol, 73%). H NMR
(C6D6, 400 MHz) δ: 7.7.42-7.38 (dd, 1H, J ) 1.55, 7.65 Hz),
7.37-7.33 (dd, 1H, J ) 1.15, 7.95 Hz), 6.97-6.91 (dt, 1H, J )
1.15, 7.5 Hz), 6.72-6.66 (dt, 1H, J ) 1.7, 7.45 Hz), 3.93-3.87
(d, 1H, J ) 14.4 Hz), 3.88-3.83 (d, 1H, J ) 14.4 Hz), 3.24-
3.17 (q, 1H, J ) 6.95 Hz), 1.90-1.81 (s, 1H), 1.35 (s, 9H),
1.1.21-1.88 (d, 3H, J ) 6.95 Hz). 13C NMR (C6D6, 100 MHz)
δ: 175.2, 1403, 133.4, 130.5, 128.9, 127.9, 128.3, 80.6, 57.5,
52.1, 28.4, 19.7 ppm. IR (neat, cm-1) ν: 3338, 3064, 2977, 1725,
1569, 1465, 1441, 1368, 1254, 1214, 1146, 1025, 849, 746. Anal.
Calcd for C14H20BrNO2: C, 53.51; H, 6.42. Found: C, 53.55;
H, 6.36.
2,3,5,6-Tetr a h yd r o-1H-p yr r olo[2,1-a ]isoqu in olin e-10b-
ca r boxylic Acid ter t-Bu tyl Ester (29) (Ta ble 2, En tr y 7).
Following the general procedure, 28 (0.177 g, 0.5 mmol) in
dioxane (2.5 mL) was allowed to react for 24 h at 90 °C using
ligand 2. Flash column chromatography (ether/hexanes 1:3)
1
yielded 29 as a yellow oil (0.097 g, 0.36 mmol, 71%). H NMR
(C6D6, 400 MHz) δ: 7.30-7.25 (m, 1H), 7.09-6.98 (m, 2H),
6.96-6.91 (m, 1H), 3.60-3.51 (ddd, 1H, J ) 4.0, 10.20 Hz,
12.70 Hz), 3.20-3.13 (ddd, 1H, J ) 2.1, 7.25, 12.20 Hz), 2.97-
2.91 (m, 1H), 2.86-2.80 (ddd, 1H, J ) 3.9, 4.9, 12.7 Hz), 2.76-
2.67 (ddd, 1H, J ) 3.9, 10.20, 15.8 Hz), 2.67-2.59 (dt, 1H, J )
6.25, 8.85 Hz), 2.49-2.41 (dt, 1H, J ) 3.8, 15.8 Hz), 1.96-
1.83 (m, 1H), 1.69-1.60 (m, 1H), 1.53-1.43 (m, 1H), 1.27 (s,
9H). 13C NMR (C6D6, 100 MHz) δ:_173.9, 140.4, 135.5, 129.3,
127.0, 126.8, 126.7, 80.2, 70.2, 53.0, 45.8, 38.8, 28.2, 25.5, 24.4
ppm. IR (neat, cm-1) ν: 2973, 2941, 2802, 1721, 1490, 1453,
1366, 1266, 1256, 1152, 1113, 1030, 974, 847, 760, 743. Anal.
Calcd for C17H23NO2: C, 74.69; H, 8.48. Found: C, 74.60; H,
8.47.
2-[N-(Ben zyloxyca r bon yl)-N-(2-br om oben zyl)]a m in o-
p r op ion ic Acid ter t-Bu tyl Ester (32). To a stirred solution
of 2-(2-bromobenzyl)aminopropionic acid tert-butyl ester (1.24
g, 3.94 mmol) in dichloromethane (5 mL) was added diisopro-
pylethylamine (0.83 mL, 4.73 mmol), followed by dropwise
addition of benzyl chloroformate (0.62 mL, 4.34 mmol). The
solution was stirred for 1 h at ambient temperature and then
submitted to an aqueous workup (water, 3× ether, brine), dried
over MgSO4, and concentrated. The crude product was purified
by flash column chromatography (ether/hexanes 1:5) yielding
32 as a colorless oil (1.4 g, 3.2 mmol, 81%) that consisted of a
1
1-[2-(2-Br om oph en yl)eth yl]piper idin e-2-car boxylic Acid
ter t-Bu tyl Ester (30). To a stirred solution of pipecolinic acid
tert-butyl ester (0.75 g, 4.1 mmol) in DMF (4 mL) and toluene
(2 mL) was added K2CO3 (1.18 mmol, 6.11 mmol), followed by
a solution of 2-bromophenethyl bromide (1.18 g, 4.48 mmol)
in DMF (2 mL). The slurry was stirred for 20 h at 80 °C, and
after being cooled to room temperature it was filtered through
silica gel and washed with ether. The organic layer was
submitted to an aqueous workup (water, 3× ether, brine), dried
over MgSO4, and concentrated. The crude product was purified
by flash column chromatography (ether:hexanes 1:5) yielding
2:1 mixture of rotamers. H NMR (C6D6, 400 MHz) δ: 7.56-
7.52 (d, 0.34H, J ) 7.55 Hz), 7.39-7.35 (d, 0.66H, J ) 7.65
Hz), 7.32-7.25 (m, 1.7H), 7.15-7.08 (m, 0.66H), 7.08-6.97 (m,
4.64H), 6.97-6.90 (m, 1H), 6.82-6.74 (m, 1.34H), 5.30-5.25
(d, 0.34H, J ) 12.5 Hz), 5.10-5.01 (m, 1.32H), 4.92-4.86 (d,
0.66H, J ) 12.5 Hz), 4.89-4.83 (d, 0.34H, J ) 17.6 Hz), 4.64-
4.57 (d, 0.34H, J ) 16.8 Hz), 4.44-4.37 (d, 0.66H, J ) 17.6
Hz), 4.30-4.24 (q, 0.66H, J ) 7.2 Hz), 4.09-4.02 (q, 0.34H, J
) 7.2 Hz), 1.34 (s, 6H), 1.25-120 (m, 5H), 0.91-0.86 (d, 1H, J
) 7.2 Hz). 13C NMR (C6D6, 100 MHz, major rotamer) δ: 171.0,
156.5, 138.5, 133.1, 129.9, 129.2, 129.0, 128.9, 128.8, 128.5,
127.9, 122.9, 81.3, 67.6, 57.4, 50.9, 32,2, 28.2 ppm. IR (neat,
cm-1) ν: 3066, 3004, 2979, 2958, 1737, 1706, 1455, 1441, 1407,
1368, 1254, 1154, 1069, 1027, 912, 849, 746, 696. Anal. Calcd
for C22H26BrNO4: C, 58.94; H, 5.85. Found: C, 59.09; H, 5.83.
2-Ben zyloxyca r b on yl-2-m et h yl-2,3-d ih yd r o-1H -isoin -
d ole-1-ca r boxylic Acid ter t-Bu tyl Ester (33) (Ta ble 3,
En tr y 1). Following the general procedure, 32 (0.195 g, 0.5
mmol) in dioxane (2.5 mL) was allowed to react for 20 h at 90
°C using ligand 3. Flash column chromatography (ether/
hexanes 1:12) yielded 33 as an orange oil (0.123 g, 0.34 mmol,
67%) that consisted of a 3:2 mixture of rotamers. 1H NMR
(C6D6, 400 MHz) δ: 7.35-7.20 (m, 2H), 7.17-6.90 (m, 6H),
6.80-6.72 (m, 1H), 5.31-5.26 (d, 0.66H, J ) 12.4 Hz), 5.29-
5.24 (d, 0.34H, J ) 12.5 Hz), 5.21-5.16 (d, 0.34H, J ) 12.5
Hz), 5.09-5.04 (d, 0.34H, J ) 14.8 Hz), 5.07-5.02 (d, 0.66H,
J ) 12.4 Hz), 4.83-4.77 (d, 0.66H, J ) 14.3 Hz), 4.80-4.73
1
30 as a colorless oil (0.86 g, 2.33 mmol, 57%). H NMR (C6D6,
400 MHz) δ: 7.39-7.35 (dd, 1H, J ) 1.15, 7.6 Hz), 7.09-7.06
(dd, 1H, J ) 1.65, 7.5 Hz), 6.92-6.87 (dt, 1H, J ) 1.2, 7.5 Hz),
6.68-6.63 (dt, 1H, J ) 1.7, 7.6 Hz), 3.21-3.12 (m, 2H), 3.03-
2.93 (m, 3H), 2.79-2.68 (m, 1H), 2.33-2.25 (ddd, 1H, J ) 3.55,
6.9, 10.8 Hz), 1.91-1.82 (m, 1H), 1.76-166 (m, 1H), 1.58-1.38
(m, 3H), 1.35 (s, 9H), 1.28-1.17 (m, 1H). 13C NMR (C6D6, 100
MHz) δ: 173.1, 140.8, 133.3, 131.6, 128.2, 127.9, 125.3, 80.2,
65.2, 56.9, 50.1, 35.0, 30.2, 28.5, 26.4, 22.8 ppm. IR (neat, cm-1
)
ν: 2935, 2856, 1725, 1472, 1443, 1366, 1291, 1210, 1148, 1115,
1100, 1030, 999, 850, 831, 748. Anal. Calcd for C18H26BrNO2:
C, 58.70; H, 7.12. Found: C, 58.53; H, 7.21.
1,2,3,4,6,7-H exa h yd r op yr id o[2,1-a ]isoq u in olin e-11b -
ca r boxylic Acid ter t-Bu tyl Ester (31) (Ta ble 2, En tr y 9).
Following the general procedure, 30 (0.184 g, 0.5 mmol) in
dioxane (2.5 mL) was allowed to react for 23 h at 90 °C using

R-Arylation of R-Amino Acid Esters
J . Org. Chem., Vol. 67, No. 2, 2002 475
(d, 0.34H, J ) 14.8 Hz), 4.54-4.48 (d, 0.66H, J ) 14.3 Hz),
1.26 (s, 6H), 1.13 (s, 3H). 13C NMR (C6D6, 100 MHz) δ: 171.4,
155.0, 142.9, 142.7, 138.0, 137.4, 137.0, 129.0, 128.9, 128.7,
128.3, 123.4, 123.2, 122.4, 122.3, 81.3, 73.0, 72.1, 67.7, 67.3,
54.4, 53.3, 28.0, 27.9, 25.1, 24.0 ppm. IR (neat, cm-1) ν: 3035,
2979, 2939, 2871, 1735, 1706, 1455, 1405, 1355, 1252, 1154,
En tr y 2). Following the general procedure, 34 (0.195 g, 0.5
mmol) in dioxane (2.5 mL) was allowed to react for 2 h at 90
°C using ligand 3. Flash column chromatography (ether/
hexanes 1:12) yielded 35 as an orange oil (0.151 g, 0.49 mmol,
99%) that consisted of a 1:1 mixture of rotamers. 1H NMR
(C6D6, 400 MHz) δ: 7.82-7.78 (m, 1H), 7.61-7.57 (m, 1H),
7.36-7.32 (m, 0.5H), 7.25-7.15 (m, 1H), 7.14-6.78 (m, 10.5H),
5.25-5.21 (d, 0.5H, J ) 12.35 Hz), 5.18-5.11 (d, 0.5H, J )
14.85 Hz), 5.10-5.05 (d, 0.5H, J ) 12.3 Hz), 5.05-5.00 (d,
0.5H, J ) 12.3 Hz), 4.98-4.93 (d, 0.5H, J ) 14.85 Hz), 4.89-
4.84 (d, 0.5H, J ) 14.45 Hz), 4.83-4.78 (d, 0.5H, J ) 12.35
Hz), 4.77-4.72 (d, 0.5H, J ) 14.45 Hz), 1.29 (s, 4.5H), 1.18 (s,
4.5H). 13C NMR (C6D6, 100 MHz) δ: 169.6, 169.6, 155.3, 154.4,
143.3, 142.8, 142.4, 141.7, 137.9, 137.8, 137.2, 136.8, 130.5,
129.5, 129.1, 129.0, 128.9, 128.8, 128.7, 128.5, 128.2, 128.0,
127.9, 127.7, 124.9, 124.8, 123.1, 123.0, 82.2, 82.0, 78.5, 77.8,
67.6, 67.4, 54.5, 53.5, 28.1, 27.9 ppm. IR (neat, cm-1) ν: 3062,
3033, 3006, 2979, 1737, 1708, 1497, 1447, 1403, 1351, 1297,
1121, 1065, 1021, 912, 847, 750, 698. Anal. Calcd for C22H25
NO4: C, 71.91; H, 6.86. Found: C, 72.10; H, 6.87.
-
N-(Ben zyloxyca r bon yl)-N-(2-br om oben zyl)p h en ylgly-
cin e ter t-Bu tyl Ester (34). To a stirred solution of 2-[N-(2-
bromobenzyl)]aminophenylacetic acid tert-butyl ester (0.38 g,
1.0 mmol) in dichloromethane (1 mL) was added diisopropyl-
ethylamine (0.19 mL, 1.1 mmol), followed by dropwise addition
of benzylchloroformate (0.15 mL, 1.05 mmol). The solution was
stirred for 1 h at ambient temperature and then submitted to
an aqueous workup (water, 3× ether, brine), dried over MgSO4,
and concentrated. The crude product was purified by flash
column chromatography (ether/hexanes 1:20) yielding 39 as
a highly viscous colorless oil (0.47 g, 0.92 mmol, 92%) that
1250, 1150, 1125, 984, 841, 746, 694. Anal. Calcd for C27H27
NO4: C, 75.50; H, 6.34. Found: C, 75.63; H, 6.34.
-
1
consisted of a ∼2:1 mixture of rotamers. H NMR (C6D6, 400
MHz) δ: 7.55-6.95 (m, 9H), 6.94-6.82 (m, 4H), 6.60-6.54 (m,
1H), 6.01-5.96 (s, 0.7H), 5.79-5.72 (s, 0.3H), 5.34-4.87 (m,
3H), 4.80-4.57 (m, 1H), 1.34 (s, 6H), 1.24 (s, 3H). 13C NMR
(C6D6, 100 MHz, major rotamer) δ:_170.1, 157.5, 138.4, 137.3,
135.2, 132.7, 130.3, 129.0, 128.9, 128.8, 128.3, 127.4, 122.6,
82.1, 68.0, 66.2, 65.2, 49.9, 28.2, 15.9 ppm, IR (neat, cm-1) ν:
3066, 3033, 2977, 2935, 1737, 1704, 1455, 1441, 1401, 1368,
1256, 1150, 1104, 1027, 970, 916, 841, 798, 746, 698. Anal.
Calcd for C27H28BrNO4: C, 63.53; H, 5.53. Found: C, 63.61;
H, 5.52.
Ack n ow led gm en t. We gratefully acknowledge sup-
port from the National Institutes of Health (GM46059)
as well as Pfizer and Merck for unrestricted funding.
O.G. thanks the Deutsche Forschungsgemeinschaft
(DFG) for a Research Fellowship.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR data of
compounds 19 and 20. This material is available free of charge
via the Internet at http://pubs.acs.org.
2-Ben zyloxyca r b on yl-1-p h en yl-2,3-d ih yd r o-1H -isoin -
d ole-1-ca r boxylic Acid ter t-Bu tyl Ester (35) (Ta ble 3,
J O0107756