Direct synthesis of Cbz-protected (2-amino)-6-(2-aminoethyl)pyridines

Article abstract of DOI:10.1016/j.tet.2010.01.025

A novel series of (2-amino)-6-(2-aminoethyl)pyridines were prepared by a convenient Suzuki-Miyaura coupling approach from 2-amino-6-bromopyridines. Benzyl vinylcarbamate was first treated with 9-BBN followed by aqueous NaOH and then the appropriate bromopyridine precursors were added into the mixture. The mixture was finally heated in presence of a palladium catalyst to provide the corresponding products in overall high yields. The procedure is extended to the preparation of related pyrazine and pyrimidine compounds as well as (2-amido)- and (2-alkoxy)-6-(2-aminoethyl)pyridines.

Full text of DOI:10.1016/j.tet.2010.01.025

Tetrahedron 66 (2010) 1973–1979
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct synthesis of Cbz-protected (2-amino)-6-(2-aminoethyl)pyridines
,
a
a
b
b
Sudipta Roya , Andrew J. Zych , R. Jason Herr , Cliff Cheng , Gerald W. Shipps, Jr.
*
a Medicinal Chemistry Department, AMRI, PO Box 15098, 26 Corporate Circle, Albany, NY 12212-5098, USA
b Lead Discovery, Schering-Plough Research Institute, 320 Bent Street, Cambridge, MA 02141, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of (2-amino)-6-(2-aminoethyl)pyridines were prepared by a convenient Suzuki–Miyaura
coupling approach from 2-amino-6-bromopyridines. Benzyl vinylcarbamate was first treated with 9-BBN
followed by aqueous NaOH and then the appropriate bromopyridine precursors were added into the
mixture. The mixture was finally heated in presence of a palladium catalyst to provide the corresponding
products in overall high yields. The procedure is extended to the preparation of related pyrazine and
pyrimidine compounds as well as (2-amido)- and (2-alkoxy)-6-(2-aminoethyl)pyridines.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 22 November 2009
Received in revised form 1 January 2010
Accepted 6 January 2010
Available online 18 January 2010
Keywords:
2-(Aminoethyl)pyridines
Aminoethylation
Suzuki–Miyaura reactions
Pd-catalyzed reactions
2-Halopyridines
CH3
1. Introduction
Br
S
O
R1
R3
H
N
N
N
N
N
N
N
N
N
H
N
The 2-amino-6-(2-aminoethyl)pyridine skeleton 1 (Fig. 1) is an
important structural motif found in various medicinally important
molecules.1 In particular, 2-aminopyridine derivatives (e.g., com-
pound 1a) are potent inhibitors of nitric oxide synthase (NOS) and
thus could be used in the treatment of NOS-related diseases e.g.,
inflammation, septic shock, rheumatoid arthritis, osteoarthritis,
Parkinson’s disease, cardiovascular diseases, allergy, cancer, obe-
sity and pain.2 2-Aminopyridines have also been shown to inhibit
apolipoprotein B (Apo B) secretion and therefore are potentially
useful in the conditions associated with elevated circulating levels
of Apo B, such as hyperlipidemia, hypertriglyceridemia, athero-
sclerosis, restenosis, pancreatitis, non-insulin dependent diabetes
mellitus and coronary heart diseases.3 Trovirdine (1b), a known
HIV-1 reverse transcriptase inhibitor, contains a 2-(2-amino-
ethyl)-pyridine subunit.4 In spite of these interesting biological
activities, only a limited number of synthetic approaches have
appeared in literature to date for the synthesis of compounds
related to 1 and therefore, a convenient and general route for the
synthesis of this heterocyclic skeleton continues to be of great
synthetic interest.
H
H
R2
H
H
CN
1
1a
Trovirdine (1b)
Figure 1. (2-Aminoethyl)pyridines.
As a part of an ongoing research program, we recently found the
need to develop a convenient and general route for the synthesis of
various N-protected (2-aminoethyl)heterocyclic compounds re-
lated to structure 1. Several routes were envisioned for the syn-
thesis of these 2-(2-aminoethyl)pyridines (Fig. 2). For example, the
synthesis of the desired compounds could be accomplished by the
addition of amines (or phthalimides)5a,6 to 2-vinylpyridines, made
in turn from either 2-halopyridines or related 2-substituted pyri-
dine derivatives (path a).5 However, the literature shows that low
yield of the desired product was encountered in many cases5b,c,7
possibly due to the formation of the bis-addition product as one of
the major byproducts.8 Alternatively, Heck reactions using an ac-
rylate followed by subsequent manipulations could afford 1 (path
b).9 Another route could be accomplished by the reduction of the
(2-cyanomethyl)pyridines that can be made directly either from
the corresponding 2-bromopyridines10 or by multiple steps via the
intermediacy of alkyl cyano(2-pyridinyl)acetates11 or 2-hal-
omethylpyridines (path c).12 Also, these 2-(2-aminoethyl)pyridines
could be synthesized from 2-(2-nitrovinyl)pyridines that, in turn,
could be prepared from 2-pyridinecarboxaldehydes using the
Henry reaction conditions (path d).13
* Corresponding author. Tel.: þ1 518 512 2000; fax: þ1 518 512 2079.
E-mail address: sudipta.roy@amriglobal.com (S. Roy).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.025

1974
S. Roy et al. / Tetrahedron 66 (2010) 1973–1979
a
e
R1
R3
R1
R1
R1
N
N
N
N
R2
N
X
N
R2
N
X
N
R2
N
H
R2
1
b
d
c
R1
R1
R1
CN
N
R2
N
NO2
N
R2
N
CO2H
N
R2
N
R1
R1
CO2R
CN
R1
R1
X
N
R2
N
N
CHO
X/H
N
R2
N
N
R2
N
CO2R
N
R2
N
N
R1
R1
R1
R1
N
CH3
N
N
N
X
N
N
X
R2
R2
R2
R2
Figure 2. Possible synthetic routes to (2-aminoethyl)pyridines.
Apart from the aforementioned methods, modern metal-cata-
lyzed cross-coupling reactions such as those developed by Negishi
or Kumada,14 or some variant of the Suzuki–Miyaura reactions15 are
attractive alternatives to attain this synthetic transformation (path
e). Although rhodium-catalyzed hydroamination reactions of
vinylpyridines16a and photo-catalyzed [2þ2þ2]-cycloaddition re-
actions of nitriles with acetylenes16b are known, these were not
considered practical for our purposes.
absent from commercial availability, and only a few syntheses have
been reported for the simple 2-(2-aminoethyl)pyridines.8a,21
Noteworthy, compared to related 3- or 4-halopyridine analogues,
many palladium-catalyzed reactions do not work well with 2-hal-
opyridines. One reason for this poor reactivity has been explained
by the propensity of ortho-palladated pyridine complex 2 to
undergo formation of more stable dimeric complex 3, effectively
removing the palladium from the catalytic cycle (Fig. 3).22
Few reports have appeared in the literature to show that a halo-
heterocycle may be directly converted into the corresponding N-
protected (2-aminoethyl)heterocycle (1, R3¼protecting group)
using a Suzuki–Miyaura cross-coupling method. This has been
achieved either by direct cross-coupling of a dialkylborane in-
termediate (generated in situ from benzyl N-vinylcarbamate)17–19
L
- L
N
Pd
N
X
L
+ L
N
Pd
L
X
Pd
L
X
or a
b
-aminoethyltrifluoroborate (made separately)20 with the
heteroaryl iodides or bromides. The original report by Kamatani
and Overman, however, describes only one example of this
2
3
Figure 3. Dimerization of (2-pyridyl)palladium complexes.
b-aminoethylation reaction involving a heterocycle where a simple
4-bromopyridine is converted to the corresponding b-aminoethyl
derivative.18 Interestingly, even after a decade, not much activity
and development have been observed using this reaction in the
field of heterocyclic chemistry and just a few examples were found
2. Results and discussion
Since a wide variety of 2-bromopyridines bearing a 6-amino
functionality are commercially available, we initially considered
a direct approach using these as starting materials. Our initial
approach involved the conversion of the 2-bromopyridine 4 into
the cyanomethyl derivative 4a using an alpha-lithiated acetoni-
trile10 followed by the reduction of the nitrile functionality
(Scheme 1). Unfortunately, our initial attempts to achieve this
direct coupling with cyanomethyl organolithium and 4 were
unsuccessful in providing the desired arylated acetonitrile 4a in
appreciable amounts. We then turned our attention from classical
anion chemistry to the modern palladium-catalyzed reactions in
order to achieve a direct synthesis of this scaffold. Toward this
direction, we attempted the direct installation of N-Boc-protected
aminoethyl functionality by preparing the zincate of tert-butyl 2-
bromoethylcarbamate, hoping to prepare 4b by inducing
a Negishi-type coupling with 4 (Scheme 1).14a However, this pal-
ladium-mediated coupling procedure was unsuccessful in our
hands.
where similar
b-aminoethylation was achieved with halides di-
rectly attached to the ring bearing the heteroatom.19 Although
recent reports by Molander and co-workers describe a similar
transformation with several bromo-heterocycles, including
unsubstituted 3-bromopyridine, the preparation of prerequisite
potassium
synthetic manipulations. Moreover, the final palladium-catalyzed
cross-coupling reaction using this potassium -amino-
b-aminoethyltrifluoroborate itself involves multiple
b
ethyltrifluoroborate with bromo-heterocycles requires RuPhos as
the phosphine ligand for a better yield of the targeted molecules
(and even to furnish the desired product in some cases).20
Although, as discussed before, this b-aminoethylation reaction
has been reported with simple unsubstituted 3-bromopyridine20
and 4-bromopyridine,18 no reports have appeared in the literature
using 2-bromopyridines in similar routes. Also, to date no sys-
tematic study has been done for the synthesis of the pyridyl com-
pounds related to structure 1. Furthermore, this motif is particularly

S. Roy et al. / Tetrahedron 66 (2010) 1973–1979
1975
Next, we focused our attention on the palladium catalyzed
Suzuki–Miyaura reactions reported by Corey–Roberts and Kama-
tani–Overman.17,18 According to the Kamatani–Overman procedure,
we first treated benzyl vinylcarbamate (15) with 9-BBN followed by
aqueous NaOH to generate the organoborane species, which was
n-BuLi/MeCN
CN
N
N
N
Br
Br
N
N
THF, -78 °C to rt
4
4a
subsequently reacted with compound
4 in the presence of
Zn, I2, Br(CH2)2NHBoc
PdCl2(dppf) at room-temperature.18 However, only small amounts
(<10%) of desired product 16 were isolated in our initial attempts.
We then followed the Suzuki–Miyaura modifications reported by
Keen and co-workers for the tetrahydropyridoazepine system.23
Using these conditions treatment of 2-bromopyridine with 15 and
9-BBN in the presence of Pd(OAc)2, dppf, and K2CO3 at 65 ꢀC did not
Boc
N
N
N
H
N
Pd(PPh3)4, DMF
rt to 80 °C
4
4b
Scheme 1. Unsuccessful initial approaches.
Table 1
Cross-coupling reactions of benzyl vinylcarbamate-derived boronates with various 6-bromo-2-aminopyridines
Entry
Bromopyridine
2-Aminoethyl Product
Yielda (%)
93
Cbz
Cbz
N
N
N
H
1
N
N
Br
Br
4
16
N
N
N
H
N
N
2
3
94
91
5
17
H3C
Cbz
H3C
N
N
N
H
N
N
Br
CH3
CH3
6
18
Cbz
H3C
N
CH3
N
N
H3C
N
CH3
N
Br
4
5
6
7
90
81
84
88b
H
7
19
Cbz
N
N
N
N
N
Br
H
O
O
8
20
Cbz
N
N
Br
N
N
N
H
N
N
H3C
H3C
21
9
Cbz
N
N
N
N
N
Br
Br
Br
H
10
22
Cbz
Cbz
8
9
75
77
N
N
N
N
N
H
N
N
23
11
N
N
N
N
H
N
N
N
12
24
H3C
Cbz
H3C
10
72
76
N
H
N
N
N
N
Br
H
H
13
25
Cbz
11
N
N
N
N
N
Br
H
H
H
14
26
a
Reactions were carried out on 2 mmol scale.
Reaction was carried out on 1 mmol scale.
b

1976
S. Roy et al. / Tetrahedron 66 (2010) 1973–1979
furnish any appreciable amount of desired product. Also, the use of
PdCl2(dppf) as the catalyst instead of the Pd(OAc)2 and dppf com-
bination in the previous case was unsuccessful. Switching back to
the hydroxide base (NaOH) and heating the reaction mixture of
organoborane and 4 with catalytic PdCl2(dppf) at 45 ꢀC were found
to be beneficial as the desired product 16 was observed to form in
appreciable amounts (>50%). Towards this direction, heating the
reaction mixture at 65 ꢀC using the previous conditions provided
the complete consumption of starting material 4. A simplified
work-up procedure was carried out to isolate the crude product
which was subsequently purified to furnish the desired product in
excellent yield (Table 1, entry 1). We also screened four other Pd-
catalysts for the reaction of bromopyridine 4 under the same
reaction conditions. Among these, Pd(PPh3)4 and PdCl2(PPh3)2
were found to be useful for this reaction; the desired product 16
was formed in 63% and 68% yields, respectively. In contrast,
Pd2(dba)3 and Pd(dba)2 were ineffective for this transformation and
only a small amount of the desired product 16 was observed in each
case. Herein, we are pleased to report the synthesis of a novel series
of aminopyridines in which the distal primary amine is protected as
a benzyl carbamate moiety.
High yields of the desired products 16–26 were obtained from
the corresponding 6-substituted-2-bromopyridine precursors 4–14,
using the previously described conditions (Scheme 2, Table 1).
Notably, 2-bromo-6-morpholinopyridine (8) and 2-bromo-6-(N-
methyl)piperazinopyridine (9) furnished the corresponding
products 20 and 21 in high yields (entries 5 and 6). Relatively lower
yields were obtained in the reactions with 2-bromo-6-imidazolo-
pyridine (11) and 2-bromo-6-pyrazolopyridine (12) as the corre-
sponding Cbz-protected (2-aminoethyl)pyridines 23 and 24 were
formed in 75% and 77% yields, respectively (entries 8 and 9). To our
delight, the monosubstituted precursors 13 and 14 also participated
in the reaction to furnish the desired products 25 and 26,
respectively (entries 10 and 11), albeit in moderate yields, but
obviating the need for an additional protection scheme.
knowledge, this is the first example of a heteroaryl chloride par-
ticipating in a
-aminoethylation reaction.
b
In summary, a novel series of N-Cbz-protected (2-amino)-6-(2-
aminoethyl)pyridines has been efficiently prepared from the
corresponding heterocyclic bromides. We also extended this
procedure to the 6-amido and 6-alkoxy variants as well as related
pyrazine and pyrimidine derivatives and also demonstrated the
use of heteroaryl chlorides for the first time in this reaction. These
results should permit easy access to similar heterocyclic systems.
3. Experimental
3.1. General
1Hand13CNMRspectrawererecordedonaBrukerUltraShield300
or 400 MHz FT-NMR spectrometer. Chemical shifts (d) are reported in
parts per million (ppm). All coupling constants (J values) are reported
in Hertz (Hz). Melting points were determined with a Mel-Temp
electrothermal apparatus and are uncorrected. Low resolution mass
spectra were recorded on a PE Sciex API 150EX mass spectrometer
equipped with a Turbo Ionspray interface. High resolution mass
spectra were obtained on a Waters MicroMass Q-TOF spectrometer.
Pyridine starting materialswere purchased from either Combi-Blocks
or CombiPhos (except 28, 29, 32, and 35 were purchased from Tyger
Scientific, Milestone PharmTech, TCI America and HDH Pharma, re-
spectively); benzyl vinylcarbamate was purchased from Organix;
PdCl2(dppf), 9-BBN (0.5 M solution in THF) and anhydrous THF were
purchased from Aldrich and were used as received. All experiments
were performed under a nitrogen atmosphere.
3.2. Representative experimental procedure
To a stirred solution of benzyl N-vinylcarbamate (15, 850 mg,
4.8 mmol) in anhydrous THF (6 mL) at 0 ꢀC under nitrogen was
added dropwise a solution of 9-borabicyclo[3.3.1]nonane (9-BBN,
0.5 M in THF, 8 mL), after which the mixture was warmed to room
temperature, stirring for a total of 16 h. The mixture was then cooled
to 0 ꢀC and 3 M aqueous sodium hydroxide solution (3.6 mL) was
slowly added dropwise. Stirring was continued for 30 min after
which time the ice-bath was removed and the mixture was warmed
to room temperature, stirring for a total of 2 h. The resulting reaction
mixture was transferred into a mixture of the 2-amino-6-bromo-
pyridine starting material (2 mmol) and PdCl2(dppf) (146 mg,
0.2 mmol) in THF (10 mL) at room temperature under nitrogen, and
the resulting mixture was degassed by bubbling nitrogen through
the reaction mixture for 15 min. The mixture was then heated to
65 ꢀC to stir for 24 h. The cooled mixture was diluted with saturated
aqueous sodium bicarbonate solution (75 mL) and then extracted
with ethyl acetate (3ꢁ100 mL). The combined organic extracts were
dried over sodium sulfate, vacuum filtered through Hyflo and the
filtrate solvents were removed under reduced pressure. The residue
was purified by Teledyne-Isco CombiFlash Companion on silica gel
to provide the desired product.
1. 9-BBN,
(15)
NHCbz
THF, 0 °C
R1
R1
Cbz
N
R2
N
Br
N
R2
N
N
H
2. aq NaOH, 0 °C to rt
3. PdCl2(dppf), THF, 65 °C
4-14
16-26
Scheme 2. 9-BBN-mediated cross-coupling reaction of benzyl N-vinylcarbamate with
2-bromopyridines 4–14.
We then applied our method to the preparation of (2-amino-
ethyl)pyridines 37–39 bearing an amido (or lactam) functionality
and 40–42 bearing ether moieties at the pyridine C-6 position
(Scheme 3, Table 2).
For all these amides (entries 1–3) and ethers (entries 4–6), the
desired products 37–42 were obtained in high yields. Extension of
this procedure to the related bromopyrazine precursor 33 (entry 7)
and bromopyrimidine 34 (entry 8) afforded the desired products 43
and 44 in excellent yields. Most importantly, chlorides 35 and 36
afforded the targeted products 45 and 46, respectively, albeit in
moderate isolated yields (entries 9 and 10). To the best of our
3.2.1. Benzyl 2-(6-(pyrrolidin-1-yl)pyridin-2-yl)ethyl carbamate (16).
Yield¼605 mg (93%), light yellow oil: 1H NMR (CDCl3, 400 MHz)
d
7.33–7.28 (m, 6H), 6.60 (br s, 1H), 6.33 (d, 1H, J¼7.2 Hz), 6.17 (d, 1H,
J¼8.4 Hz), 5.09 (s, 2H), 3.56 (q, 2H, J¼5.7 Hz), 3.41 (t, 4H, J¼6.4 Hz),
1. 9-BBN,
(15)
2.79 (t, 2H, J¼5.9 Hz), 1.96–1.93 (m, 4H); 13C NMR (CDCl3, 100 MHz)
A
N
NHCbz
A
N
A
A
A
A
THF, 0 °C
d
158.1, 156.8, 156.5, 137.5, 137.1, 128.5, 127.9, 127.8, 110.3, 104.2, 66.3,
Cbz
Y
X
Y
N
H
46.6, 40.5, 36.4, 25.5; LRMS (ESIþ) m/z 326 [MþH]þ; HRMS (ESIþ)
calcd for C19H24N3O2 [MþH]: 326.1869, found 326.1854.
2. aq NaOH, 0 °C to rt
3. PdCl2(dppf), THF, 65 °C
27-36
37-46
(A = CH, N; X = Br, Cl; Y = OR, NR2, NHCOR, 2-pyrrolidinone)
3.2.2. Benzyl 2-(6-(piperidin-1-yl)pyridin-2-yl)ethylcarbamate (17).
Yield¼638 mg (94%), light yellow oil: 1H NMR (CDCl3, 400 MHz)
Scheme 3. 9-BBN-mediated cross-coupling reaction of benzyl N-vinylcarbamate with
heteroaryl halides related to 4.
d
7.35–7.28 (m, 6H), 6.46 (d,1H, J¼8.5 Hz), 6.38 (d,1H, J¼7.2 Hz), 5.97

S. Roy et al. / Tetrahedron 66 (2010) 1973–1979
1977
Table 2
Cross-coupling reactions of benzyl vinylcarbamate-derived boronates with representative 2-halopyridines and related compounds
Entry
Bromopyridine
2-Aminoethyl Product
Yielda (%)
O
O
Cbz
N
N
N
H
1
86
N
N
Br
27
37
O
O
Cbz
2
3
4
76
91
90
H3C
N
H
N
Br
H3C
N
H
N
N
H
38
28
O
O
Cbz
(H3C)3C
H3C
N
H
N
Br
(H3C)3C
H3C
N
H
N
N
H
39
29
Cbz
O
N
N
O
N
Br
H
30
40
CH3
O
CH3
O
Cbz
5
6
92
H3C
N
Br
H3C
N
N
H
41
31
85b
Cbz
O
N
Br
O
N
N
H
42
32
N
N
H3C
H3C
Cbz
Cbz
N
CH3
N
Br
Br
Cl
N
CH3
N
N
H
7
8
9
91
82
53
43
33
N
N
H3C
H3C
H3C
H3C
N
CH3
N
N
H
N
CH3
N
34
44
N
N
Cbz
Cbz
N
CH3
N
N
CH3
N
N
H
45
35
N
N
N
N
Cl
10
N
N
N
H
56
46
36
a
Reactions were carried out on 1 mmol scale.
Reaction was carried out on 2 mmol scale.
b
(br s,1H), 5.07 (s, 2H), 3.56 (q, 2H, J¼6.0 Hz), 3.49–3.48 (m, 4H), 2.79
5.09 (s, 2H), 3.58–3.50 (m, 4H), 2.98 (s, 3H), 2.79 (t, 2H, J¼6.0 Hz),
(t, 2H, J¼6.1 Hz), 1.59 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d
159.3,
1.10 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3, 75 MHz)
d 158.0, 157.7, 156.5,
157.5, 156.5, 138.0, 136.9, 128.5, 127.9, 127.5, 127.0, 111.7, 104.9, 66.4,
46.3, 40.3, 36.9, 25.5, 24.8; LRMS (ESIþ) m/z 340 [MþH]þ, HRMS
(ESIþ) calcd for C20H26N3O2 [MþH]: 340.2025, found 340.2029.
137.7, 137.0, 128.5, 127.9, 127.0, 110.5, 103.4, 66.4, 44.6, 40.3, 36.8,
35.5, 11.9; LRMS (ESIþ) m/z 314 [MþH]þ; HRMS (ESIþ) calcd for
C18H24N3O2 [MþH]: 314.1869, found 314.1873.
3.2.3. Benzyl
2-(6-(dimethylamino)pyridin-2-yl)ethylcarbamate
3.2.5. Benzyl 2-(6-morpholinopyridin-2-yl)ethylcarbamate (20).
Yield¼551 mg (81%), colorless oil: 1H NMR (CDCl3, 400 MHz)
(18). Yield¼545 mg (91%), colorless oil: 1H NMR (CDCl3, 400 MHz)
d
7.37–7.28 (m, 6H), 6.38–6.34 (m, 2H), 6.11 (br s,1H), 5.09 (s, 2H), 3.59
d 7.42–7.29 (m, 6H), 6.51–6.45 (m, 2H), 5.80 (br s, 1H), 5.08 (s, 2H),
(q, 2H, J¼5.9 Hz), 3.05 (s, 6H), 2.82 (t, 2H, J¼6.0 Hz); 13C NMR (CDCl3,
3.76 (t, 4H, J¼4.7 Hz), 3.57 (q, 2H, J¼6.0 Hz), 3.45 (t, 4H, J¼4.9 Hz),
100 MHz)
d
159.0, 157.6, 156.6, 137.8, 137.1, 128.5, 128.0, 127.0, 110.8,
2.83 (t, 2H, J¼6.2 Hz); 13C NMR (CDCl3, 100 MHz)
d 159.2, 157.6,
103.7, 66.4, 40.4, 38.2, 36.8; LRMS (ESIþ) m/z 300 [MþH]þ; HRMS
156.4, 138.2, 136.8, 128.5, 128.1, 113.2, 104. 7, 66.7, 66.5, 45.6, 40.2,
37.0; LRMS (ESIþ) m/z 342 [MþH]þ; HRMS (ESIþ) calcd for
C19H24N3O3 [MþH]: 342.1818, found 342.1820.
(ESIþ) calcd for C17H22N3O2 [MþH]: 300.1712, found 300.1713.
3.2.4. Benzyl 2-(6-(ethyl(methyl)amino)pyridin-2-yl)ethylcarbamate
(19). Yield¼564 mg (90%), light yellow oil: 1H NMR (CDCl3,
3.2.6. Benzyl 2-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)ethylcarba-
300 MHz)
d
7.34–7.29 (m, 6H), 6.32 (t, 2H, J¼7.8 Hz), 6.16 (br s, 1H),
mate (21). Yield¼595 mg (84%), light brown oil: 1H NMR (CDCl3,

1978
S. Roy et al. / Tetrahedron 66 (2010) 1973–1979
300 MHz)
d
7.40–7.30 (m, 6H), 6.46 (t, 2H, J¼7.1 Hz), 5.92 (br s, 1H),
HRMS (ESIþ) calcd for C19H22N3O3 [MþH]: 340.1661, found
5.08 (s, 2H), 3.60–3.50 (m, 6H), 2.82 (t, 2H, J¼6.2 Hz), 2.45 (t, 4H,
340.1657.
J¼4.9 Hz), 2.30 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 159.0, 157.6,
156.4, 138.1, 136.9, 128.5, 128.0, 127.9, 112.6, 104.8, 66.5, 54.9, 46.2,
45.2, 40.2, 36.9; LRMS (ESIþ) m/z 355 [MþH]þ; HRMS (ESIþ) calcd
for C20H27N4O2 [MþH]: 355.2134, found 355.2122.
3.2.13. Benzyl 2-(6-acetamidopyridin-2-yl)ethylcarbamate (38).
Yield¼239 mg (76%), off-white solid: mp 86–88 ꢀC; 1H NMR (CDCl3,
300 MHz)
d
8.21 (br s, 1H), 8.02 (d, 1H, J¼7.8 Hz), 7.57 (t, 1H,
J¼7.9 Hz), 7.32 (s, 5H), 6.84 (d, 1H, J¼7.4 Hz), 5.34 (br s, 1H), 5.16–
5.08 (m, 2H), 3.56 (q, 2H, J¼6.2 Hz), 2.86 (t, 2H, J¼6.5 Hz), 2.17 (s,
3.2.7. Benzyl 2-(6-(1H-pyrrol-1-yl)pyridin-2-yl)ethylcarbamate
(22). Yield¼282 mg (88%), light yellow oil: 1H NMR (CDCl3,
3H); 13C NMR (CDCl3, 75 MHz)
d 168.9, 157.6, 156.5, 151.1, 138.9,
300 MHz)
d
7.57 (t, 1H, J¼7.9 Hz), 7.48 (t, 2H, J¼2.3 Hz), 7.32–7.28
136.7, 128.6. 128.2, 119.3, 111.6, 66.7, 40.2, 37.4, 24.7; LRMS (ESIþ) m/
z 314 [MþH]þ; HRMS (ESIþ) calcd for C17H20N3O3 [MþH]: 314.1505,
found 314.1494.
(m, 5H), 7.09 (d, 1H, J¼8.2 Hz), 6.88 (d, 1H, J¼7.4 Hz), 6.32 (t, 2H,
J¼2.3 Hz), 5.46 (br s, 1H), 5.07 (s, 2H), 3.63 (q, 2H, J¼6.1 Hz), 2.94 (t,
2H, J¼6.3 Hz); 13C NMR (CDCl3, 75 MHz)
d 158.6, 156.4, 150.8, 139.0,
136.7, 128.5, 128.0, 119.7, 118.0, 111.3, 109.0, 66.6, 40.0, 37.1; LRMS
(ESIþ) m/z 322 [MþH]þ; HRMS (ESIþ) calcd for C19H20N3O2 [MþH]:
322.1556, found 322.1562.
3.2.14. Benzyl 2-(6-pivalamidopyridin-2-yl)ethylcarbamate (39).
Yield¼324 mg (91%), colorless oil: 1H NMR (CDCl3, 400 MHz)
d 8.08
(d, 1H, J¼8.3 Hz), 7.98 (br s, 1H), 7.58 (t, 1H, J¼7.9 Hz), 7.32–7.29 (m,
5H), 6.86 (d, 1H, J¼7.4 Hz), 5.25 (br s, 1H), 5.08 (s, 2H), 3.57 (q, 2H,
J¼6.3 Hz), 2.88 (t, 2H, J¼6.5 Hz), 1.31 (s, 9H); 13C NMR (CDCl3,
3.2.8. Benzyl 2-(6-(1H-imidazol-1-yl)pyridin-2-yl)ethylcarbamate
(23). Yield¼481 mg (75%), light yellow oil: 1H NMR (CDCl3,
100 MHz) d 177.1, 157.4, 156.4, 151.2, 138.9, 136.7, 128.6, 128.1, 119.2,
400 MHz)
d
8.29 (s, 1H), 7.68 (t, 1H, J¼7.8 Hz), 7.61 (s, 1H), 7.32–7.27
111.7, 66.7, 40.3, 39.8, 37.4, 27.5; LRMS (ESIþ) m/z 356 [MþH]þ;
HRMS (ESIþ) calcd for C20H26N3O3 [MþH]: 356.1974, found
356.1972.
(m, 5H), 7.15–7.14 (m, 2H), 7.06 (d, 1H, J¼7.5 Hz), 5.59 (br s, 1H), 5.08
(s, 2H), 3.65 (q, 2H, J¼6.2 Hz), 3.01 (t, 2H, J¼6.4 Hz); 13C NMR
(CDCl3, 100 MHz)
d 159.3, 156.4, 148.5, 139.4, 136.6, 134.8, 130.5,
128.5, 128.0, 121.6, 116.1, 109.9, 66.5, 39.9, 37.3; LRMS (ESIþ) m/z 323
[MþH]þ; HRMS (ESIþ) calcd for C18H19N4O2 [MþH]: 323.1508,
found 323.1513.
3.2.15. Benzyl 2-(6-methoxypyridin-2-yl)ethylcarbamate (40).
Yield¼258 mg (90%), colorless oil: 1H NMR (CDCl3, 300 MHz)
d
7.46–7.41 (m,1H), 7.31–7.26 (m, 5H), 6.67 (d,1H, J¼7.2 Hz), 6.56 (d,
1H, J¼8.3 Hz), 5.67 (br s, 1H), 5.08 (s, 2H), 3.88 (s, 3H), 3.59 (q, 2H,
3.2.9. Benzyl 2-(6-(1H-pyrazol-1-yl)pyridin-2-yl)ethylcarbamate
J¼6.1 Hz), 2.87 (t, 2H, J¼6.3 Hz); 13C NMR (CDCl3, 75 MHz)
d 163.7,
(24). Yield¼495 mg (77%), light yellow solid: mp 44–46 ꢀC; 1H
157.0, 156.4, 139.0, 136.8, 128.5, 128.0, 115.9, 108.3, 66.5, 53.2, 40.2,
36.8; LRMS (ESIþ) m/z 287 [MþH]þ; HRMS (ESIþ) calcd for
C16H19N2O3 [MþH]: 287.1396, found 287.1395.
NMR (CDCl3, 300 MHz)
d
8.53 (dd, 1H, J¼2.6 Hz, 0.5 Hz), 7.81 (d, 1H,
J¼8.0 Hz), 7.72–7.66 (m, 2H), 7.35–7.30 (m, 6H), 7.00 (d,
1H, J¼7.4 Hz), 6.43–6.41 (m, 1H), 5.33 (br s, 1H), 5.09 (s, 2H), 3.67 (q,
2H, J¼6.2 Hz), 2.99 (t, 2H, J¼6.4 Hz); 13C NMR (CDCl3, 100 MHz)
3.2.16. Benzyl 2-(6-isopropoxypyridin-2-yl)ethylcarbamate (41).
Yield¼290 mg (92%), light yellow oil: 1H NMR (CDCl3, 400 MHz)
d
158.0, 156.5, 151.2, 142.1, 139.3, 136.7, 128.6, 128.2, 127.0, 121.1,
110.2, 107.8, 66.7, 40.1, 37.2; LRMS (ESIþ) m/z 323 [MþH]þ; HRMS
d
7.45–7.41 (m,1H), 7.34–7.29 (m, 5H), 6.64 (d,1H, J¼7.2 Hz), 6.51 (d,
(ESIþ) calcd for C18H19N4O2 [MþH]: 323.1508, found 323.1516.
1H, J¼8.3 Hz), 5.66 (br s,1H), 5.27–5.22 (m,1H), 5.09 (s, 2H), 3.59 (q,
2H, J¼6.0 Hz), 2.86 (t, 2H, J¼6.2 Hz), 1.31 (d, 6H, J¼6.2 Hz); 13C NMR
3.2.10. Benzyl 2-(6-(methylamino)pyridin-2-yl)ethylcarbamate
(CDCl3, 100 MHz) d 163.1, 157.0, 156.5, 139.1, 136.9, 128.5, 128.1,
(25). Yield¼409 mg (72%), light yellow solid: mp 82–84 ꢀC; 1H
115.5, 109.2, 67.9, 66.6, 40.3, 36.9, 22.1; LRMS (ESIþ) m/z 315
[MþH]þ; HRMS (ESIþ) calcd for C18H23N2O3 [MþH]: 315.1709,
found 315.1703.
NMR (CDCl3, 400 MHz)
d
7.33–7.28 (m, 6H), 6.40 (d, 1H, J¼7.2 Hz),
6.20 (d, 1H, J¼8.3 Hz), 5.90 (br s, 1H), 5.08 (s, 2H), 4.60 (br s, 1H),
3.55 (q, 2H, J¼6.0 Hz), 2.85 (d, 3H, J¼5.2 Hz), 2.78 (t, 2H, J¼6.2 Hz);
13C NMR (CDCl3, 100 MHz)
d
159.3, 157.9, 156.5, 138.0, 136.9, 128.5,
3.2.17. Benzyl 2-(6-(benzyloxy)pyridin-2-yl)ethylcarbamate (42).
Yield¼614 mg (85%), colorless oil: 1H NMR (CDCl3, 300 MHz)
128.1, 128.0, 112.1, 103.9, 66.5, 40.4, 37.0, 29.1; LRMS (ESIþ) m/z 286
[MþH]þ; HRMS (ESIþ) calcd for C16H20N3O2 [MþH]: 286.1556,
found 286.1546.
d
7.48–7.25 (m, 11H), 6.69–6.62 (m, 2H), 5.44 (br s, 1H), 5.34 (s, 2H),
5.07 (s, 2H), 3.58 (q, 2H, J¼6.1 Hz), 2.87 (t, 2H, J¼6.2 Hz); 13C NMR
(CDCl3, 75 MHz)
d 163.2, 156.9, 156.4, 139.2, 137.5, 136.8, 128.5,
3.2.11. Benzyl 2-(6-(cyclohexylamino)pyridin-2-yl)ethylcarbamate
128.1, 127.8, 116.3, 108.9, 67.5, 66.6, 40.1, 36.9; LRMS (ESIþ) m/z 363
[MþH]þ; HRMS (ESIþ) calcd for C22H23N2O3 [MþH]: 363.1709,
found 363.1701.
(26). Yield¼537 mg (76%), light brown oil: 1H NMR (CDCl3,
300 MHz)
d
7.35–7.25 (m, 6H), 6.35 (d, 1H, J¼7.2 Hz), 6.18 (d, 1H,
J¼8.3 Hz), 5.90 (br s, 1H), 5.09 (s, 2H), 4.40 (d, 1H, J¼6.4 Hz), 3.58–
3.48 (m, 3H), 2.77 (t, 2H, J¼6.1 Hz), 2.02–1.98 (m, 2H), 1.72–1.68 (m,
2H), 1.60–1.56 (m, 1H), 1.39–1.10 (m, 5H); 13C NMR (CDCl3, 75 MHz)
3.2.18. Benzyl 2-(6-(dimethylamino)pyrazin-2-yl)ethylcarbamate
(43). Yield¼273 mg (91%), light brown oil: 1H NMR (CDCl3,
d
158.1, 157.8, 156.5, 137.9, 137.0, 128.5, 128.2, 128.1, 111.7, 104.8, 66.6,
300 MHz) d 7.84 (s, 1H), 7.64 (s, 1H), 7.32–7.30 (m, 5H), 5.69 (br s,
50.4, 40.5, 37.0, 33.5, 25.9, 25.0; LRMS (ESIþ) m/z 354 [MþH]þ;
HRMS (ESIþ) calcd for C21H28N3O2 [MþH]: 354.2182, found
354.2182.
1H), 5.09 (s, 2H), 3.59 (q, 2H, J¼6.1 Hz), 3.07 (s, 6H), 2.81 (t, 2H,
J¼6.3 Hz); 13C NMR (CDCl3, 75 MHz)
d 156.4, 154.2, 151.4, 136.8,
130.8, 128.5, 128.0, 127.7, 66.5, 39.9, 37.5, 34.3; LRMS (ESIþ) m/z 301
[MþH]þ; HRMS (ESIþ) calcd for C16H21N4O2 [MþH]: 301.1665,
found 301.1663.
3.2.12. Benzyl 2-(6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)ethylcarba-
mate (37). Yield¼292 mg (86%), off-white solid: mp 85–87 ꢀC; 1H
NMR (CDCl3, 400 MHz)
d
8.22 (d, 1H, J¼8.4 Hz), 7.57 (t, 1H,
3.2.19. Benzyl 2-(2-(dimethylamino)pyrimidin-4-yl)ethylcarbamate
J¼7.9 Hz), 7.32–7.27 (m, 5H), 6.86 (d, 1H, J¼7.3 Hz), 5.74 (br s, 1H),
5.08 (s, 2H), 4.05 (t, 2H, J¼7.1 Hz), 3.60 (q, 2H, J¼5.9 Hz), 2.91 (t, 2H,
J¼6.1 Hz), 2.61 (t, 2H, J¼8.1 Hz), 2.07–2.00 (m, 2H); 13C NMR (CDCl3,
(44). Yield¼246 mg (82%), off-white solid: mp 93–95 ꢀC; 1H
NMR (CDCl3, 400 MHz)
d
8.08 (d, 1H, J¼6.2 Hz), 7.34–7.28
(m, 5H), 6.25 (d, 1H, J¼6.2 Hz), 5.91 (br s, 1H), 5.09 (s, 2H), 3.65
100 MHz) d 174.9, 157.2, 156.4, 151.3, 138.1, 136.8, 128.5, 128.0, 118.8,
(q, 2H, J¼5.9 Hz), 3.07 (s, 6H), 2.95 (t, 2H, J¼6.0 Hz); 13C NMR
112.2, 66.5, 47.3, 40.0, 36.8, 33.6,17.5; LRMS (ESIþ) m/z 340 [MþH]þ;
(CDCl3, 100 MHz) d 167.8, 161.9, 156.4, 155.2, 137.0, 128.5, 128.1,

S. Roy et al. / Tetrahedron 66 (2010) 1973–1979
1979
128.0, 100.3, 66.5, 39.0, 38.5, 37.0; LRMS (ESIþ) m/z 301 [MþH]þ;
HRMS (ESIþ) calcd for C16H21N4O2 [MþH]: 301.1665, found
301.1667.
Appl. WO 93/03022, 1993; (c) Zhang, H.; Vrang, L.; Rydergaard, C.; Aahgren, C.;
Oeberg, B. Antiviral Chem. Chemother. 1996, 7, 221–229.
5. (a) Han, X.; Civiello, R. L.; Mercer, S. E.; Macor, J. E.; Dubowchik, G. M. Tetra-
hedron Lett. 2009, 50, 386–388; (b) Showalter, H. D. H. J. Heterocycl. Chem. 2006,
43, 1311–1317; (c) Cogan, D.; Hao, M.-H.; Kamhi, V.M.; Miller, C.A.; Netherton,
M.R.; Swinamer, A.D. PCT Int. Appl. WO 2005/090333, 2005; (d) Albanese, D.;
Ghidoli, C.; Zenoni, M. Org. Process Res. Dev. 2008, 12, 736–739; (e) Schulz, W.;
Pracejus, H.; Oehme, G. J. Mol. Catal. 1991, 66, 29–36.
6. (a) Zhang, Y.; Liang, H.-C. Molecules 2006, 11, 163–168; (b) Chaturvedula, P.V.;
Mercer, S.E.; Fang, H.; Han, X.; Luo, G.; Dubowchik, G.M.; Poindexter, G.S.U.S.
Patent US 7,470,680, 2008; (c) Jones, P.; Pryde, D.C.; Tran, T.D. PCT Int. Appl. WO
2007/093901, 2007; (d) Kirchner, F. K.; McCormick, J. R.; Cavallito, C. J.; Miller,
L. C. J. Org. Chem. 1949, 14, 388–393; (e) Bhanushali, M. J.; Nandurkar, N. S.;
Bhor, M. D.; Bhanage, B. M. Catal. Commun. 2007, 9, 425–430.
7. (a) Kunishita, A.; Kubo, M.; Sugimoto, H.; Ogura, T.; Sato, K.; Takui, T.; Itoh, S.
J. Am. Chem. Soc. 2009, 131, 2788–2789; (b) Chen, C. W.; Tran, J. A.; Fleck, B.
A.; Tucci, F. C.; Jiang, W.; Chen, C. Bioorg. Med. Chem. Lett. 2007, 17, 6825–6831.
8. (a) Ladomenou, K.; Charalambidis, G.; Coutsolelos, A. G. Tetrahedron 2007, 63,
2882–2887; (b) Gonschior, M.; Kotteritzsch, M.; Rost, M.; Schonecker, B.;
Wunderwald, M. Tetrahedron: Asymmetry 2000, 11, 2159–2182.
9. (a) Collot, V.; Varlet, D.; Rault, S. Tetrahedron Lett. 2000, 41, 4363–4366; (b)
Kline, T.; Sieber-McMaster, E.; Lau, W. F.; Natarajan, S. Bioorg. Med. Chem. Lett.
1997, 7, 1017–1020; (c) Alberico, D.; Rudolph, A.; Lautens, M. J. Org. Chem. 2007,
72, 775–781; (d) Dickinson, R. P.; Dack, K. N.; Long, C. J.; Steele, J. J. Med. Chem.
1997, 40, 3442–3452; (e) Kaul, R.; Deechongkit, S.; Kelly, J. W. J. Am. Chem. Soc.
2002, 124, 11900–11907; (f) Deechongkit, S.; Powers, E. T.; You, S.-L.; Kelly, J. W.
J. Am. Chem. Soc. 2005, 127, 8562–8570.
10. (a) Skerlj, R. T.; Bogucki, D.; Bridger, G. J. Synlett 2000, 1488–1490; (b) New-
kome, G. R.; Joo, Y. J.; Evans, D. W.; Pappalardo, S.; Fronczek, F. R. J. Org. Chem.
1988, 53, 786–790; (c) Gyorkos, A.C.; Corrette, C.P.; Cho, S.Y.; Turner, T.M.; Aso,
K.; Kori, M.; Gyoten, M.; Condroski, K.R.; Siedem, C.S.; Boyd, S.A. PCT Int. Appl.
WO 2005/099688, 2005.
11. (a) Coqueron, P.-Y.; Desbordes, P.; Mansfield, D.J.; Rieck, H.; Grosjean-Cournoyer,
M.-C.; Villier, A.; Genix, P. Eur. Pat. Appl. EP 1 548 007, 2005; (b) Mansfield, D.J.;
Coqueron, P.-Y.; Desbordes, P.; Rieck, H.; Grosjean-Cournoyer, M.-C.; Genix, P.;
Villier, A.; Christian, I. Eur. Pat. Appl. EP 1 500 651, 2005; (c) Desideri, N.; Manna,
F.; Stein, M. L. J. Heterocycl. Chem. 1988, 25, 333–335; (d) Fukuda, Y. PCT Int.
Appl. WO 2005/005398, 2005.
3.2.20. Benzyl 2-(4-(dimethylamino)pyrimidin-2-yl)ethylcarbamate
(45). Yield¼160 mg (53%), light brown solid: mp 95–97 ꢀC; 1H
NMR (DMSO-d6, 300 MHz)
d
8.07 (d, 1H, J¼6.2 Hz), 7.39–7.23 (m,
6H), 6.47 (d, 1H, J¼6.2 Hz), 5.01 (s, 2H), 3.45–3.35 (m, 2H), 3.03 (s,
6H), 2.78 (t, 2H, J¼7.4 Hz); 13C NMR (DMSO-d6, 75 MHz)
d 166.6,
161.5, 156.0, 155.0, 137.2, 128.3, 127.7, 127.6, 100.4, 65.1, 36.4; LRMS
(ESIþ) m/z 301 [MþH]þ; HRMS (ESIþ) calcd for C16H21N4O2 [MþH]:
301.1665, found 301.1659.
3.2.21. Benzyl 2-(4-(pyrrolidin-1-yl)pyrimidin-2-yl)ethylcarbamate
(46). Yield¼182 mg (56%), light brown solid: mp 105–107 ꢀC; 1H
NMR (DMSO-d6, 400 MHz)
d
8.05 (d, 1H, J¼6.0 Hz), 7.38–7.24 (m,
6H), 6.28 (d, 1H, J¼6.1 Hz), 5.01 (s, 2H), 3.43–3.34 (m, 6H), 2.77 (t,
2H, J¼7.4 Hz), 1.93–1.88 (m, 4H); 13C NMR (DMSO-d6, 100 MHz)
d
166.9, 159.3, 156.0, 154.5, 137.2, 128.3, 127.7, 127.6, 101.4, 65.1, 45.8;
LRMS (ESIþ) m/z 327 [MþH]þ; HRMS (ESIþ) calcd for C18H23N4O2
[MþH]: 327.1821, found 327.1825.
Acknowledgements
We thank Drs. Bruce F. Molino and Michael Guaciaro for their
help and support of this work, Drs. Brian Gregg and Matthew Voss
for useful discussion and AMRI MedChem Scientific Advisory
Committee for reviewing the manuscript.
12. (a) Bombi, G. G.; Aikebaier, R.; Dean, A.; Di Marco, V. B.; Marton, D.; Tapparo, A.
Polyhedron 2009, 28, 327–335; (b) Vyvyan, J. R.; Brown, R. C.; Woods, B. P. J. Org.
Chem. 2009, 74, 1374–1376; (c) Butini, S.; Campiani, G.; Borriello, M.; Gemma,
S.; Panico, A.; Persico, M.; Catalanotti, B.; Ros, S.; Brindisi, M.; Agnusdei, M.;
Fiorini, I.; Nacci, V.; Novellino, E.; Belinskaya, T.; Saxena, A.; Fattorusso, C. J. Med.
Chem. 2008, 51, 3154–3170; (d) Binyamin, I.; Pailloux, S.; Duesler, E. N.; Rapko,
B. M.; Paine, R. T. Inorg. Chem. 2006, 45, 5886–5892; (e) Jung, F.H.; Morgentin, R.
R.; Ple, P. PCT Int. Appl. WO 2007/099323, 2007. (f) Jung, F.H.; Ple, P. PCT Int.
Appl. WO 2007/099317, 2007.
Supplementary data
1H and 13C NMR spectra of all compounds prepared. Supple-
mentary data associated with this article can be found, in the online
version, at doi:10.1016/j.tet.2010.01.025.
References and notes
13. (a) Butler, T.W. PCT. Int. Appl. WO 2006/048727, 2006; (b) Cantrell, A. S.; En-
gelhardt, P.; Hoegberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordan, C. L.;
Kangasmetsae, J.; Kinnick, M. D.; Lind, P. J. Med. Chem. 1996, 39, 4261–4274; (c)
Chandrasekhar, S.; Reddy, N. R.; Rao, Y. S. Tetrahedron 2006, 62, 12098–12107;
(d) Shigehisa, H.; Takayama, J.; Honda, T. Tetrahedron Lett. 2006, 47, 7301–7306;
(e) Batra, S.; Sabnis, Y. A.; Rosenthal, P. J.; Avery, M. A. Bioorg. Med. Chem. 2003,
11, 2293–2299.
14. (a) Berna, J.; Crowley, J. D.; Goldup, S. M.; Haenni, K. D.; Lee, A.-L.; Leigh, D. A.
Angew. Chem., Int. Ed. 2007, 46, 5709–5713; (b) Jackson, R. F. W.; Wishart, N.;
Wood, A.; James, K.; Wythes, M. J. J. Org. Chem. 1992, 57, 3397–3404; (c) Snider,
B. B.; Neubert, B. J. Org. Lett. 2005, 7, 2715–2718.
15. (a) Miyaura, N.;Ishiyama, T.;Sasaki, H.;Ishikawa,M.;Sato, M.;Suzuki, A. J. Am.Chem.
Soc. 1989, 111, 314–321; (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
16. (a) Utsunomiya, M.; Kuwano, R.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 5608–5609; (b) Heller, B.; Sundermann, B.; Buschmann, H.; Drexler,
H.-J.; You, J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002, 67,
4414–4422.
17. Corey, E. J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8919–8920.
18. (a) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743–8744; (b) Kama-
tani, A.; Overman, L. E. Org. Lett. 2001, 3, 1229–1232.
1. (a) Keenan, R. M.; Miller, W. H.; Barton, L. S.; Bondinell, W. E.; Cousins, R. D.;
Eppley, D. F.; Hwang, S.-M.; Kwon, C.; Lago, M. A.; Nguyen, T. T.; Smith, B. R.;
Uzinskas, I. N.; Yuan, C. C. K. Bioorg. Med. Chem. Lett. 1999, 9, 1801–1806; (b)
Vacher, B.; Bonnaud, B.; Funes, P.; Jubault, N.; Koek, W.; Assie, M.-B.; Cosi, C.
J. Med. Chem. 1998, 41, 5070–5083; (c) Jadhav, P.K.; Petraitis, J.J.; Batt, D.G.U.S.
Patent 5,760,028, 1998; (d) Santora, V.; Askew, B.; Ghose, A.; Hague, A.; Kim,
T.S.; Laber, E.; Li, A.; Lian, B.; Liu, G.; Norman, M.H.; Smith, L.; Tasker, A.;
Tegley, C.; Yang, K. PCT Int. Appl. WO 02/14311, 2002; (e) Asao, T.; Yamashita,
T.; Suda, Y.; Okajima, S.; Tada, Y.; Katsunuma, N.; Yamada, S.; Shigeno, K.;
Uemura, A. PCT Int. Appl. WO98/47887, 1998; (f) Kohara, T.; Fukunaga, K.;
Hanano, T. PCT Int. Appl. WO 2004/014910, 2004.
2. (a) Connolly, S.; Cox, D. PCT Int. Appl. WO 00/021934, 2000; (b) Esser, C.K.;
Hagmann, W.K.; Hoffman, W.F.; Shah, S.K.; Wong, K.K.; Chabin, R.M.; Guthi-
konda, R.K.; MacCoss, M.; Caldwell, C.G.; Durette, P.L. PCT Int. Appl. WO 96/
18616, 1996; (c) Chabrier De Lassauniere, P.-E.; Auvin, S.; Harnett, J.; Pons, D.;
Ulibarri, G.; Bigg, D. PCT Int. Appl. WO 00/02860, 2000; (d) Kawano, E.; Nagai,
M.; Inubushi, A.; Shimada, K.; Tobari, H. PCT Int. Appl. WO97/09982, 1997; (e)
Garcin, E. D.; Arvai, A. S.; Rosenfeld, R. J.; Kroeger, M. D.; Crane, B. R.; Andersson,
G.; Andrews, G.; Hamley, P. J.; Mallinder, P. R.; Nicholls, D. J.; St-Gallay, S. A.;
Tinker, A. C.; Gensmantel, N. P.; Mete, A.; Cheshire, D. R.; Connolly, S.; Stuehr, D.
J.; Aberg, A.; Wallace, A. V.; Tainer, J. A.; Getzoff, E. D. Nature Chem. Biol. 2008, 4,
700–707; (f) Fang, J.; Ji, H.; Lawton, G. R.; Xue, F.; Roman, L. J.; Silverman, R. B.
J. Med. Chem. 2009, 52, 4533–4537.
19. (a) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677–680; (b) Parrot, I.; Ritter, G.;
Wermuth, C. G.; Hibert, M. Synlett 2002, 1123–1127.
20. (a) Molander, G. A.; Vargas, F. Org. Lett. 2007, 9, 203–206; (b) Molander, G. A.;
Jean-Ge´rard, L. J. Org. Chem. 2007, 72, 8422–8426.
21. (a) Magnus, G.; Levine, R. J. Am. Chem. Soc. 1956, 78, 4127–4130; (b) Taki, M.;
Teramae, S.; Nagatomo, S.; Tachi, Y.; Kitagawa, T.; Itoh, S.; Fukuzumi, S. J. Am.
Chem. Soc. 2002, 124, 6367–6377; (c) Reich, H. E.; Levine, R. J. Am. Chem. Soc.
1955, 77, 5434–5436; (d) Barluenga, J.; Montserrat, J. M.; Florez, J. Tetrahedron
Lett. 1992, 33, 6183–6186; (e) Sakamoto, T.; Nagata, H.; Kondo, Y.; Sato, K.;
Yamanaka, H. Chem. Pharm. Bull. 1984, 32, 4866–4872; (f) Ivanov, I.; Karagiozov,
S.; Sulai, P. Arch. Pharmacol. 1989, 322, 181–182.
22. Bozell, J. J.; Vogt, C. E.; Gozum, J. J. Org. Chem. 1991, 56, 2584–2587.
23. Keen, S. P.; Cowden, C. J.; Bishop, B. C.; Brands, K. M. J.; Davies, A. J.; Dolling, U.
H.; Lieberman, D. R.; Stewart, G. W. J. Org. Chem. 2005, 70, 1771–1779.
3. (a) Takasugi, H.; Inoue, Y.; Terasawa, T.; Nagayoshi, A.; Furukawa, Y.; Mikami,
M.; Hinoue, K.; Ohtsubo, M.; Fukumoto, D. PCT Int. Appl. WO 03/045921, 2003;
(b) Takasugi, H.; Terasawa, T.; Inoue, Y.; Nakamura, H.; Nagayoshi, A.; Ohtake,
H.; Furukawa, Y.; Mikami, M.; Hinoue, K.; Ohtsubo, M. PCT Int. Appl. WO 02/
28835, 2002; (c) Inoue, Y.; Terasawa, T.; Takasugi, H.; Nagayoshi, A.; Ueshima,
K.; Sawada, M.; Furukawa, Y.; Mikami, M.; Hinoue, K.; Fukumoto, D. PCT Int.
Appl. WO 2004/039795, 2004.
4. (a) Ahgren, C.; Backro, K.; Bell, F. W.; Cantrell, A. S.; Clemens, M.; Colacino, J. M.;
Deeter, J. B.; Engelhardt, J. A.; Hogberg, M. Antimicrob. Agents Chemother. 1995,
39, 1329–1335; (b) Lind, P.T.; Morin, J.M.; Noreen, R.; Ternansky, R.J. PCT Int.