N-arylation of carbamate-protected glycine derivatives via palladium catalysis

Article abstract of DOI:10.1016/j.tetlet.2014.03.016

A synthesis of N-aryl and N-heteroaryl amino acid derivatives using palladium catalysis is described. Several carbamate-protected glycine derivatives react with aryl and heteroaryl halides using a palladium/Xantphos catalyst system to access the desired synthons.

Full text of DOI:10.1016/j.tetlet.2014.03.016

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-arylation of carbamate-protected glycine derivatives via palladium
catalysis
⇑
Danielle Falcone, Ekundayo Osimboni, David J. Guerin
Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of N-aryl and N-heteroaryl amino acid derivatives using palladium catalysis is described. Sev-
eral carbamate-protected glycine derivatives react with aryl and heteroaryl halides using a palladium/
Xantphos catalyst system to access the desired synthons.
Received 24 February 2014
Accepted 4 March 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Amino acid
Palladium
Amination
Catalysis
Hydantoin
The development of synthetic methodology to access unnatural
amino acid derivatives enables the fields of target-oriented synthe-
sis, peptide design, as well as medicinal chemistry.1 Specifically,
oligomers of N-aryl amino acid synthons have received interest
from the peptide design field for their ability to adopt well-defined
secondary structures.2 In addition, N-heteroaryl functionalized
amino esters have been prepared as b-strand mimetics (e.g., 1,
Fig. 1).3 In the context of a recent drug discovery program, we
sought to develop a facile palladium-catalyzed amination protocol
to access N-arylated amino ester and amide derivatives. Described
herein is the development of a palladium/Xantphos catalyzed
amination reaction of aryl halides with carbamate protected
amino acid derivatives to afford the corresponding N-arylated
products.
Palladium catalyzed amination of aryl halides is one of the most
efficient methods to construct amino functionalized arenes and
heteroarenes.4 Several elegant protocols have been developed that
allow for the synthesis of a broad range of structural chemotypes
by varying the nature of the aryl/heteroaryl halide and the amine
nucleophile. At the outset of our work, there were only a few
examples present in the literature describing an efficient N-aryla-
tion of amino acid derivatives.5,6 For our work, we envisioned using
carbamate protected amino ester and amide derivatives as the
nucleophilic component of the reaction (Scheme 1). The use of car-
bamate protecting groups, such as tert-butyl (Boc) or benzyl (Cbz)
carbamates, would enable further synthetic manipulation and also
allow for facile removal should the free amine be desired.
In 2000, Buchwald and co-workers described the development
of a palladium/Xantphos catalyst system for the efficient intermo-
lecular N-arylation of various amide derivatives.7 We felt that the
reactivity of a carbamate protected amino acid derivative might
be similar to that of certain amide derivatives described in this Let-
ter. In fact, the ethyl carbamate of ethylamine was found to be a
competent nucleophile for this reaction.7a Encouraged by this prec-
edent, we sought to explore the possibility of using these condi-
tions in an amination reaction with a carbamate protected amino
ester or amide derivative as the nucleophilic partner (Eq. 1). Grat-
ifyingly, a smooth reaction occurred between the methyl ester of
Boc-glycine methyl ester (3a) and methyl 4-bromobenzoate (2a)
in the presence of Pd2(dba)3, Xantphos, and Cs2CO3 as the base to
afford the corresponding N-arylated amino ester (4a) in 75%
isolated yield.
⇑
Corresponding author. Tel.: +1 617 992 2060; fax: +1 617 992 2406.
E-mail address: david_guerin@merck.com (D.J. Guerin).
http://dx.doi.org/10.1016/j.tetlet.2014.03.016
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Falcone, D.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.03.016

2
D. Falcone et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Boc
N
O
Pd2(dba)3 (2 mol%)
Xantphos (6 mol%)
Br
O
Me
H
O
N
Me
(1)
Boc
O
MeO2C
Cs2CO3 (2.0 Equiv)
dioxane, 100 oC
12 h
MeO2C
75%
2a
1.0 equiv.
3a
4a
1.5 equiv.
In an effort to define the aryl halide scope of this reaction, sev-
eral aryl and heteroaryl halides were chosen for further study8 (Ta-
ble 1). Other aryl bromides possessing electron withdrawing
substituents in the para position also work well under these condi-
tions. 1-Bromo-4-(trifluoromethyl) benzene (2b) and 4-bro-
mobenzonitrile (2c) react to afford the corresponding N-aryl
amino esters in 57% and 80% isolated yield, respectively (Table 1,
entries 1 and 2). A secondary amide in the para position affords
product 4d in lower yield (21%, Table 1, entry 3). Bicyclic aromatic
and heteroaromatic systems such as 2-bromonaphthalene and 3-
bromoquinoline afford products 4e and 4f in modest yields, 30%
and 33% respectively (Table 1, entries 4 and 5). 6-Bromoquinoline
reacts to deliver product 4g in slightly higher yield (41%, Table 1,
entry 6), while 6-bromoquinoxaline was found to be the best sub-
strate of this class (69%, Table 1, entry 7). 3-Bromopyridine fails to
yield the desired product (data not shown), but the addition of a
fluorine substituent in the 5-position results in a productive ami-
nation reaction to afford the corresponding product in 23% isolated
yield (Table 1, entry 8). The activated heteroaryl bromides 2-
bromopyrazine and 2-bromopyridine react efficiently9 to afford
products 4j and 4k in 82% and 69% yield, respectively (Table 1, en-
tries 9 and 10). In comparison, 2-chloropyridine also reacts under
these reaction conditions, albeit in only 21% isolated yield (Table 1,
entry 11). While electron poor aryl/heteroaryl halides react readily,
electron-neutral or electron-rich substrates (e.g., 4-bromotoluene;
data not shown) fail to undergo productive coupling.
Me
Me
Ac
N
O
N
H
N
H
Me
O
O
1
Figure 1. b-Strand mimetic.
R
O
O
Ar
or
Het
X
H
N
"palladium catalyst"
O
O
O
R
Y
N
X
O
Ar
Y
2
3
4
Scheme 1. Palladium catalyzed amination strategy.
Table 1
Aryl/heteroaryl halide scopea
2 mol % Pd2(dba)3
6 mol % Xantphos
Ar-X
O
Boc
N
O
H
N
or
Het-X
Boc
O
Cs2CO3 (2.0 equiv.)
Ar
O
dioxane, 100 o
C
2
3a
4
We next turned our attention to exploring the scope of the car-
bamate nucleophile.10 For this study, we chose methyl 4-bro-
mobenzoate 2a as a representative aryl halide substrate. The
benzyl carbamate 3b was found to be a competent nucleophile
Entry
1
Halide
Isolated yieldb (%)
Br
2b
2c
57
F3 C
NC
Br
2
3
80
21
Table 2
Nucleophile scopea
Br
H
N
2d
O
O
O
H
N
Me
Br
Br
Me
2 mol % Pd2(dba)3
6 mol % Xantphos
O
O
O
O
R1
R2
4
5
2e
2f
30
33
R1
O
O
N
R2
Br
Cs2CO3 (2.0 equiv.)
dioxane, 100 o
C
2a
3
5
N
Entry
1
Nucleophile
Isolated yieldb (%)
51
Br
Br
O
H
6
7
8
9
2g
2h
2i
41
69
23
82
3b
3c
N
N
N
Me
Cbz
O
O
Boc
N
Me
2
3
57
64
N
F
O
H
Br
O
H
N
3d
N
Boc
N
O
N
Br
O
H
2j
N
N
N
Me
Me
Boc
N
O
4
5
3e
3f
33
65
Br
Cl
10
11
2k
2l
69
21
O
H
Me
N
Me
Me
N
Boc
N
H
a
a
Reaction conditions: 2a (1.0 equiv), nucleophile (1.5 equiv), Pd2(dba)3 (2 mol %),
Reaction conditions: ArX/HetX (1.0 equiv), 3a (1.5 equiv), Pd2(dba)3 (2 mol %),
Xantphos (6 mol %), Cs2 CO3 (2.0 equiv), dioxane (10 mL/g halide), 100 °C, 12 h.
Xantphos (6 mol %), Cs2 CO3 (2.0 equiv), dioxane (10 mL/g halide), 100 °C, 12 h.
b
b
Isolated yield, reported as the average of two experiments.
Isolated yield, reported as the average of 2 experiments.
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D. Falcone et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 3
biologically relevant peptidomimetics and other chemotherapeutic
agents.
Typical experimental procedure: A mixture of methyl 4-bro-
mobenzoate 2a (100 mg, 0.465 mmol), methyl N-(tert-butoxycar-
bonyl)glycinate 3a (132 mg, 0.698 mmol), Pd2(dba)3 (8.5 mg,
Tandem N-arylation/cyclization to afford substituted hydantoinsa
O
H
Pd2(dba)3 (2 mol %)
Xantphos (6 mol%)
Ar
or
X
Ar
t-Bu-O
N
R
N
O
N
H
(2)
Het
X
N
R
O
Cs2CO3 (2.0 equiv.)
O
dioxane, 100 o
12 hr
C
9.3 lmol), Xantphos (16 mg, 0.028 mmol), and cesium carbonate
2
3
6
(303 mg, 0.930 mmol) was charged with dioxane (1.0 mL). The
resulting suspension was sparged with argon via subsurface bub-
bling for 5 min, and the reaction mixture was sealed and stirred
at 100 °C for 12 h. The reaction was cooled to ambient tempera-
ture, diluted with EtOAc (ꢀ20 mL), and filtered to remove the inor-
ganic salts. The filtrate was concentrated to an oil, then purified by
column chromatography on silica gel, eluting with an EtOAc/hex-
anes gradient (2–30%) to afford the desired product 4a as a color-
less gum (75% isolated yield). 1H NMR (500 MHz, DMSO-d6): d 7.90
(d, J = 9.0 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 4.39 (s, 2H), 3.83 (s, 3H),
3.68 (s, 3H), 1.37 (s, 9H). LRMS (ESI) calcd for C16H21NO6 (M+Na)+:
346.1, found: 346.1.
1.0 equiv.
1.5 equiv.
Entry
Amide
Isolated yieldb (%)
40
O
O
H
N
Me
1
2
3
3g
3h
Boc
N
H
H
N
Me
Me
Me
Me
19
Boc
N
H
O
O
H
N
3i
3j
38c
0
Boc
N
H
H
N
Ph
4
Boc
N
H
Acknowledgements
a
Reaction conditions: ArX/HetX (1.0 equiv), 3 (1.5 equiv), Pd2(dba)3 (2 mol %),
Xantphos (6 mol %), Cs2 CO3 (2.0 equiv), dioxane (10 mL/g halide), 100 °C, 12 h.
We would like to thank our colleague Jason Katz for helpful
discussions as well as Christopher Dinsmore, Jared Cumming, and
Jason Imbriglio for their helpful review of this manuscript.
b
Isolated yield, reported as the average of two experiments.
c
After microwave irradiation at 150 °C for 30 min.
under the reaction conditions, delivering product 5b in 51% iso-
lated yield (Table 2, entry 1). The homologated b-amino ester sub-
strate 3c affords the desired coupling product 5c in 57% isolated
yield (Table 2, entry 2). Glycine amide derivatives were found to
be effective coupling partners as well. The morpholine amide 3d
reacts to afford the desired adduct 5d in 64% yield (Table 2, entry
3). The Weinreb amide substrate 3e reacts in modest yield (33%,
Table 2, entry 4), potentially allowing access to the corresponding
aldehyde or ketone synthons. The sterically demanding secondary
N-tert-butylamide 3f reacts exclusively at the carbamate nitrogen
to yield 5f in 65% yield (Table 2, entry 5).
In an attempt to couple the less-hindered N-propylamide sub-
strate 3g, an unexpected tandem N-arylation/cyclization sequence
occurred to afford the N-aryl hydantoin derivative 6g (Table 3, en-
try 1). Other amide nucleophiles can undergo this transformation
to afford the corresponding hydantoins (Table 3).11 Interestingly,
the isopropyl amide 3i reacts to afford a mixture of the initial
C–N adduct and the cyclized product. However upon microwave
irradiation of the reaction mixture the initial adduct can be con-
verted further to the desired hydantoin in acceptable yield (Table 3,
entry 3). An apparent limitation of this protocol is that the N-phe-
nyl amide 3j does not undergo productive coupling to afford the
desired C–N adduct, and at this time it is unclear why the initial
palladium-mediated reaction does not proceed.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.03.
016.
References and notes
1. For a current review on this topic, see: Perdih, A.; Dolenc, M. S. Curr. Org. Chem.
2007, 11, 801–832.
2. Shah, N. H.; Butterfoss, G. L.; Nguyen, K.; Yoo, B.; Bonneau, R.; Rabenstein, D. L.;
Kirschenbaum, K. J. Am. Chem. Soc. 2008, 130, 16622–16632.
3. Blomberg, D.; Brickmann, K.; Kihlberg, J. Tetrahedron 2006, 62, 10937–10944.
4. Selected reviews: (a) Hartwig, J. F. Synlett 1997, 329–340; (b) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805–818.
5. For a palladium/copper cocatalyzed N-arylation of unprotected amino acids,
see: Xu, L.-W.; Xia, C.-G.; Li, J.-W.; Li, F.-W.; Zhou, S.-L. Catal. Commun. 2004, 5,
121–123.
6. For a copper-promoted N-arylation using carbamate protected amino esters,
see: Renger, B. Synthesis 1985, 9, 856–860.
7. (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101–1104; (b) Yin, J.; Buchwald, S.
L. J. Am. Chem. Soc. 2002, 124, 6043–6048.
8. All of the aryl and heteroaryl halides used in this study were obtained from
commercial sources and were used without further purification.
9. The control reactions performed in the absence of palladium catalyst and
Xantphos did not afford product, ruling out an SnAr-type mechanism for these
two substrates.
10. The nucleophiles used in this study were either obtained from commercial
sources and used without further purification, or prepared using standard
amide coupling conditions.
In summary, we have developed a protocol whereby various
electron poor aryl/heteroaryl halides undergo efficient
palladium-catalyzed amination reactions using amino ester/amide
synthons to afford the corresponding N-aryl derivatives. Further
manipulation of these building blocks could provide access to
11. For
a recent review on the synthesis of hydantoins, see: Meusel, M.;
Guetschow, M. Org. Prep. Proced. Int. 2004, 36, 391–443; For a review on the
pharmacologic properties of hydantoins, see: Jones, G. L.; Wimbish, G. H.
Handb. Exp. Pharmacol. 1985.
Please cite this article in press as: Falcone, D.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.03.016