Rearrangement of N,N-di-tert-butoxycarbonylpyridin-4-amines and formation of polyfunctional pyridines

Article abstract of DOI:10.1021/jo800854d

(Chemical Equation Presented) N,N-Di-tert-butoxycarbonylpyridin-4-amines were found to be rearranged to tert-butyl 4-(tert-butoxycarbonylamino) nicotinates by treatment with LDA in THF.

Full text of DOI:10.1021/jo800854d

SCHEME 1. Formation of Polysubstituted Pyridine 4a
Rearrangement of
N,N-Di-tert-butoxycarbonylpyridin-4-amines and
Formation of Polyfunctional Pyridines
Yahua Liu, Qiang Ding, and Xu Wu*
Genomics Institute of the NoVartis Research Foundation,
San Diego, California 92121
xwu@gnf.org
ReceiVed April 18, 2008
describe a unique method for the preparation of polyfunctional
pyridines based on a novel rearrangement of N,N-di(tert-
butoxycarbonyl)pyridin-4-amines (2) to tert-butyl 4-(tert-bu-
toxycarbonylamino)nicotinate (5).
During the course of our medicinal chemistry program we
sought to prepare 4-amino-2,6-dichloronicotinic acid from
4-amino-2,6-chloropyridine (1a) following a reaction sequence
described by Jang et al.4 The amino group of 1a was intended
to be protected as a tert-butoxycarbonyl group (Boc), using
sodium bis(trimethylsilyl)amide (NaHMDS) and di-tert-butyl
dicarbonate (Boc2O) in THF. However, in our hands the reaction
was very sluggish and thus an excess of NaHMDS (2.3 equiv)
and Boc2O (2.2 equiv) were used to completely consume 1a.
Unexpectedly, the only product obtained after 16 h at 25 °C
was N,N-di-tert-butoxycarbonyl-2,6-dichloropyridin-4-amine
(2a) (Scheme 1). We then decided to utilize this material to
make 4-(bis(tert-butoxycarbonyl)amino)-2,6-dichloronicotinic
acid (3a). Treatment of 2a with lithium diisopropylamide (LDA)
and quenching by the addition of an excess of dry ice led to
the formation of a product in 64% yield. Much to our surprise,
1H NMR and LC-MS data of this product did not correspond
to 3a.5 1H NMR in DMSO-d6 of this product exhibited two
distinctive singlets at 1.42 and 1.51 ppm (each intergrating to
9 protons), suggesting the presence of two different tert-butyl
groups, and it lacked any peak corresponding to the aromatic
proton. Thus, we assigned the product as 5-(tert- butoxycarbo-
nyl)-4-(tert-butoxycarbonylamino)-2,6-dichloronicotinic acid
(4a).
N,N-Di-tert-butoxycarbonylpyridin-4-amines were found to
be rearranged to tert-butyl 4-(tert-butoxycarbonylamino)ni-
cotinates by treatment with LDA in THF.
Pyridines represent key structural components of numerous
pharmacological agents and natural products.1 In addition,
polyfunctional pyridines are versatile intermediates and building
blocks used for the synthesis of pharmaceutically relevant or
biologically active heterocyclic compounds.2 Accordingly, the
development of efficient synthetic methods for the construction
of polyfunctional pyridines is of considerable importance from
the perspectives of both medicinal chemistry and organic
chemistry. Various strategies have been developed for the
synthesis of polyfunctional substituted pyridines.3 Herein we
(1) For some reviews, see:(a) Lukevits, E. Chem. Heterocycl. Compd. 1995,
31, 639–650. (b) Plunkett, A. O. Nat. Prod. Rep. 1994, 11, 581. (c) Pinder,
A. R. Nat. Prod. Rep. 1992, 9, 491. (d) Wang, C. L. J.; Wuonola, M. A. Org.
Prep. Proced. 1992, 24, 585. (e) Numata, A.; Ibuka, T. The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1987; Vol. 31. (f) Daly, J. W.; Spande,
T. F. Alkaloids: Chemical and Biological RespectiVes; Pelletier, S. W., Ed.;
Willey: New York, 1980; Vol. 4, p 1. (g) Micetich, R. G. Pyridine and Its
DeriVatiVes: Supplement; Abramovitch, R., Ed.; John Wiley and Sons: New York,
1974.
We postulated that, upon treatment with LDA, one of the
Boc groups of 2a migrated from the nitrogen atom to one of
the nonsubstituted adjacent carbon atoms of the pyridine ring
(2) For some recent examples, see:(a) Jang, M-Y.; De Jonghe, S.; Gao, L-J.;
Rozenski, J.; Herdewijn, P. Eur. J. Org. Chem. 2006, 4257. (b) Szczepankiewicz,
B. G.; Kosogof, C.; Nelson, L. T. J.; Liu, G.; Liu, B.; Zhao, H.; Serby, M. D.;
Xin, Z.; Liu, M.; Gum, R. J.; Haasch, D. L.; Wang, S.; Clampit, J. E.; Johnson,
E. F.; Lubben, T. H.; Stashko, M. A.; Olejniczak, E. T.; Sun, C.; Dorwin, S. A.;
Haskins, K.; Abad-Zapatero, C.; Fry, E. H.; Hutchins, C. W.; Sham, H. L.;
Rondinone, C. M.; Trevillyan, J. M. J. Med. Chem. 2006, 49, 3563. (c) Hu, L.;
Li, Z.; Wang, Y.; Wu, Y.; Jiang, J.; Boykin, D. Bioorg. Med. Chem. Lett. 2007,
17, 1193. (d) Liu, G.; Zhao, H.; Liu, B.; Xin, Z.; Liu, M.; Kosogof, C.;
Szczepankiewicz, B. G.; Wang, S.; Clampit, J. E.; Gum, R. J.; Haasch, D. L.;
Trevillyan, J. M.; Sham, H. L. Bioorg. Med. Chem. Lett. 2006, 16, 5723. (e) Li,
R.; Xue, L.; Zhu, T.; Jiang, Q.; Cui, X.; Yan, Z.; McGee, D.; Wang, J.; Gantla,
V. R.; Pickens, J. C.; McGrath, D.; Chucholowski, A.; Morris, S. W.; Webb,
T. R. J. Med. Chem. 2006, 49, 1006. (f) Hong, F.; Hollenback, D.; Singer, J. W.;
Klein, P. Bioorg. Med. Chem. Lett. 2005, 15, 4703. (g) Zhou, W.; Yerkes, N.;
Chruma, J. J.; Liu, L.; Breslow, R. Bioorg. Med. Chem. Lett. 2005, 15, 1351.
(3) For some examples, see:(a) Dash, J.; Lechel, T.; Reissig, H.-U. Org. Lett.
2007, 9, 5541. (b) Hogimori, M.; Mizuyama, N.; Hisadome, Y.; Nagaoka, J.;
Ueda, K.; Tominaga, Y. Tetrahedron 2007, 63, 2511. (c) Catozzi, N.; Bromley,
W.; Wasnaire, P.; Gibson, M.; Taylor, R. J. K. Synlett 2007, 2217. (d) Abu-
Shanab, F. A.; Hessen, A. M.; Mousa, S. A. S. J. Heterocycl. Chem. 2007, 44,
787. (e) Park, D. Y.; Lee, M. J.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2005,
46, 8799. (f) Kaminski, T.; Gros, P.; Fort, Y. Eur. J. Org. Chem. 2003, 3855.
(g) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J. Tetrahedron Lett. 1996,
26, 4577. (h) Cocco, M. T.; Conjiu, C.; Onnis, V. Heterocycles 1993, 36, 2829.
(i) Kniezo, L.; Kristian, P.; Imrich, J. Tetrahedron 1988, 44, 543.
(4) Jang, M-Y.; De Jonghe, S.; Gao, L-J.; Herdewijn, P. Tetrahedron Lett.
2006, 8917.
(5) We expected that 1H NMR in DMSO-d6 of 3a should have a singlet
peak for the two Boc groups (intergrating to 18 protons) and one peak for the
aromatic proton.
10.1021/jo800854d CCC: $40.75
Published on Web 07/09/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6025–6028 6025

TABLE 1. Rearrangement of N,N-Di-Boc-pyridin-4-amines (2)
SCHEME 2. LDA Treatment of a Mixture of
N,N-Di-Boc-pyridin-4-amines (2) and
N-Boc-pyridin-4-amines (10)
entry
2
R1
Cl
Cl
Br
R2
5 (%)
6 (%)
1
2
3
4
2a
2b
2c
2d
Cl
H
H
H
5a (96)
5b (90)
5c (87)
5d (0)
n/a
6b (5)
6c (3)
6d (3)
t-Bu
TABLE 2. LDA Treatment of N,N-Di-Boc-pyridin-3-amines (7)
SCHEME 3. Proposed Mechanism for the Rearrangement
entry
7
R1
R2
8 (%)
9 (%)
1
2
3
7a
7b
7c
Cl
Cl
H
Cl
H
Cl
8a (0)
8b (0)
8c (0)
9a (49)
9b (62)
9c (71)
and that the tert-butyl ester moiety did not arise from the
presence of CO2. To test this postulation, pyridine 2a was treated
with LDA in THF at -78 °C in the absence of CO2 (Table 1,
R1 ) R2 ) Cl). After 20 min, monitoring the reaction by TCL
clearly indicated the disappearance of 2a and the formation of
chloropyridin-4-amine (10b) (Scheme 2). The reaction resulted
in the formation of 5a as the exclusive product, along with the
recovery of unreacted 10b. Similarly, when subjected to the
same rearrangement condition, N-tert-butoxycarbonyl-2,6-
dichloropyridin-4-ylcarbamate (10a) remained unreacted, while
2b rearranged to form 5b and 6b. These results suggest that
the rearrangement is an intramolecular process.
1
a new product. H NMR (DMSO-d6) of the product showed
two singlets at 1.38 and 1.47 ppm (each intergrating to 9
protons) and another singlet at 7.49 ppm (intergrating to 1
proton). The NH peak at 9.8 ppm was confirmed by HMBC. A
ROE cross-peak between the NH and the unsubstituted carbon
adjacent to the Boc-amino group was also present in the ROESY
spectrum. Therefore, the product was assigned as tert-butyl
4-(tert-butoxycarbonylamino)-2,6-dichloronicotinate (5a), which
also correlates with the HRMS data.
This method was extended to several N,N-di-tert-butoxycar-
bonylpyridin-4-amines (2) for the synthesis of polysubstituted
pyridines (Table 1). In the cases where R1 and R2 are different
groups, the reaction gave regioisomers 5 and 6. For reasons
unknown, unsymmetrical 2b and 2c gave sterically encumbered
isomers 5a and 5b as major products, respectively. When R1 is
a bulky tert-butyl group, 6d was obtained in 3% yield and
formation of 5d was not observed in this case.
To gain a better understanding about the scope and utility of
this process, the rearrangement of N,N-di-tert-butoxycarbon-
ylpyridin-3-amines (7) was also explored (Table 2). However,
after several attempts under the same rearrangement reaction
conditions with different substrates 7a-c, it was found that the
rearrangement did not occur in this type of pyridine ring system.
The only products obtained from the reactions were mono-Boc-
protected 3-aminopyridines 9a-c, which means that one Boc
group was depleted during the operations.
Since the reaction happens readily for the formation of the
ortho product, we believe that it is most likely an intramolecular
reaction.6 To gain evidence to support an intramolecular over
intermolecular mechanism, we carried out the rearrangement
reaction of 2a in the presence of N-tert-butoxycarbonyl-2-
Fries-type rearrangement of aryl ester, N-arylamides, O-aryl
carbamates, and N-aryl carbamates under ultraviolet irradiation
has been well documented.7 For base-induced Fries reactions,
there are reports about metal-promoted rearrangement of O-aryl
carbamates.8 Very interestingly, Miah and Snieckus reported a
heterocyclic version of the metal-promoted Fries reaction, a
rearrangement of metalated O-pyridyl carbamates under a
condition of sec-BuLi/TMEDA/THF at -78 °C.9 The reaction
we described here is Fries rearrangement of N-pyridyl carbam-
ates. The tentative mechanism (Scheme 3) initially involves
deprotonation at the carbon adjacent to the di-Boc-amino group
of 2 by a strong base LDA, resulting in a carbonion that is
stabilized by an electron-deficient carbonyl group nearby.
Subsequent nucleophilic attack takes place at the Boc carbonyl
carbon, resulting in the migration of one Boc group to the
pyridine ring, thereby relieving steric hindrance around the
(6) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry; John
Wiley and Sons: New York, 2007; p 735.
(7) For examples, see:(a) Anderson, J. C.; Reese, C. B. J. Chem Soc. 1963,
1781. (b) Kobsa, H. J. Org. Chem. 1962, 27, 2293. (c) Elad, D.; Rao, D. V.;
Stenberg, V. I. J. Org. Chem. 1965, 30, 3252. (d) Trecker, D. J.; Foote, R. S.;
Osborn, C. L. Chem. Commun. 1968, 1034.
(8) (a) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935. (b) Miller,
J. A. J. Org. Chem. 1987, 52, 322.
(9) Miah, M. A. J.; Snieckus, V. J. Org. Chem. 1985, 50, 5436.
6026 J. Org. Chem. Vol. 73, No. 15, 2008

(CDCl3) δ 27.8, 83.8, 124.0, 135.0, 138.1, 148.8, 149.9, 150.7; ESI-
TOF HRMS calcd for [C15H21ClN2O4 + H]+ 329.1263, found
329.1270.
nitrogen atom. In terms of mechanism, it is similar to a migration
ofBocofo-bromo-N,N-di-Boc-anilinepromotedbyametal-halogen
exchange.10
tert-Butyl 2,6-Dichloropyridin-4-ylcarbamate (10a). A similar
procedure with 1.2 equiv of Boc2O afforded 10a. 1H NMR (CDCl3)
δ 1.53 (s, 9 H), 6.74 (br s, 1H, NH), 7.33 (s, 2H); 13C NMR (CDCl3)
δ 28.0, 82.6, 110.9, 149.5, 150.9, 151.4; ESI-TOF HRMS calcd
for [C10H12Cl2N2O2 + H]+ 263.0349, found 263.0351.
tert-Butyl 2-Chloropyridin-4-ylcarbamate (10b). A similar
procedure with 1.2 equiv of Boc2O afforded 10b. 1H NMR (CDCl3)
δ 1.51 (s, 9 H), 6.84 (br s, 1H, NH), 7.15 (dd, J ) 5.6 and 2.0 Hz,
1H), 7.50 (d, J ) 2.0 Hz, 1H), 8.19 (d, J ) 5.6 Hz, 1H); 13C NMR
(CDCl3) δ 28.1, 82.1, 111.3, 112.1, 147.9, 149.8, 151.6, 152.3; ESI-
TOF HRMS calcd for [C10H13ClN2O2 + H]+ 229.0738, found
229.0738.
In conclusion, we have discovered a rearrangement of N,N-
di-tert-butoxycarbonylpyridin-4-amines (2) to polysubtituted
pyridine derivatives tert-butyl 4-(tert-butoxycarbonylamino)ni-
cotinates (5). It provides a facile method for construction of
polysubstituted pyridines. Further chemical manipulations of
these highly functionalized pyridines are being carried out to
probe their usefulness for the synthesis of various nitrogen-
containing heterocyclic compounds.
Experimental Section
Representative Procedure for the Preparation of 2, 7, and
10: 4-[(Di-tert-butoxycarbonyl)amino]-2,6-dichloropyridine (2a).
A solution of 2,6-dichloropyridin-4-amine (1a) (7.50 g, 46.0 mmol)
in dry THF (300 mL) under dry N2 was cooled to 0 °C with an
ice-water bath. To this mixture was added a solution of NaHMDS
in THF (1.0 M, 106.0 mL, 106.0 mmol) via syringe. After the
reaction mixture was stirred at 0 °C for 20 min, a solution of Boc2O
(22.09 g, 101.2 mmol) in THF (100 mL) was added and the
ice-water bath then was removed. After the reaction mixture was
stirred at 25 °C for 16 h, it was poured into a 25% aqueous NH4Cl
solution (500 mL) followed by addition of EtOAc (200 mL). The
biphasic layers were separated and the aqueous phase was washed
with EtOAc (2 × 200 mL). The combined organic phases were
washed with a 20% aqueous Na2CO3 solution (40 mL) and brine
(40 mL), dried over MgSO4, and evaporated to result in a residue
that was subjected to chromatography (hexanes/EtOAc ) 19:1) to
afford 2a (16.1 g, 96% yield). 1H NMR (CDCl3) δ 1.63 (s, 18 H),
5-(tert-Butoxycarbonyl)-4-(tert-butoxycarbonylamino)-2,6-
dichloronicotinic Acid (4a). To dry THF (300 mL) under dry N2
cooled to -78 °C with a dry ice-acetone bath were sequentially
added dry diisopropylamine (8.50 mL, 6.07 g, 60.0 mmol) and a
solution of n-BuLi in hexanes (2.5 M, 22.0 mL, 55.0 mmol) via
syringe. After allowing this mixture to stir at -78 °C for 20 min,
a solution of 2a (9.08 g, 25.0 mmol) in dry THF (50 mL) was
added via syringe. After the reaction mixture was stirred for another
30 min, an excess amount of dry ice (freshly washed with hexanes)
was added and the resulting mixture was allowed to warm to 25
°C over a period of 1.5 h. The reaction mixture was then poured
into a 25% aqueous NH4Cl solution (600 mL) followed by addition
of EtOAc (200 mL). The biphasic layers were separated and the
aqueous phase was washed with EtOAc (2 × 200 mL). The
combined organic phases were washed with brine (2 × 40 mL),
dried over MgSO4, and evaporated to result in a residue that was
subjected to chromatography (DCM/MeOH/28% aqueous NH3 )
90:10:1) to afford 4a in ammonium salt form (6.8 g, 64% yield).
1H NMR (DMSO-d6) δ 1.42 (s, 9H), 1.51 (s, 9H); 13C NMR
(DMSO-d6) δ 28.1, 28.3, 81.4, 82.8, 122.6, 127.2, 144.8, 145.9,
147.0, 151.2, 161.8, 163.8; ESI-TOF HRMS calcd for
[C16H20Cl2N2O6 + H]+ 407.0771, found 407.0781.
Representative Procedure for the Rearrangement of 2:
Formation of tert-Butyl 4-(tert-butoxycarbonylamino)-2,6-
dichloronicotinate (5a). To dry THF (200 mL) under dry N2 cooled
to -78 °C with a dry ice-acetone bath were sequentially added
dry diisopropylamine (22.0 mL, 15.7 g, 155.0 mmol) and a solution
of n-BuLi in hexanes (2.5 M, 63.0 mL, 155.0 mmol) via syringe.
After allowing this mixture to stir at -78 °C for 20 min, a solution
of 2a (16.1 g, 44.3 mmol) in dry THF (50 mL) was added via
syringe. After the reaction mixture was stirred for another 20 min,
it was poured into a 25% aqueous solution of NH4Cl solution (600
mL) followed by addition of EtOAc (200 mL). The biphasic layers
were separated and the aqueous phase was washed with EtOAc (2
× 200 mL). The combined organic phases were washed with a
20% aqueous solution of Na2CO3 (40 mL) and brine (40 mL), dried
over MgSO4, and evaporated resulting in a residue that was
subjected to chromatography (hexanes/EtOAc ) 9:1) to afford 5a
(15.45 g, 96% yield). 1H NMR (CDCl3) δ 1.52 (s, 9 H), 1.62 (s, 9
H), 8.33 (s, 1H), 8.98 (br s, 1H, NH); 1H NMR (DMSO-d6) δ 1.38
(s, 9 H), 1.47 (s, 9 H), 7.49 (s, 1H), 9.80 (s, 1H, NH); 13C NMR
(DMSO-d6) δ 27.8, 27.9, 81.5, 83.5, 114.7, 118.9, 147.8, 148.5,
149.5, 151.7, 162.6; ESI-TOF HRMS calcd for [C15H20Cl2N2O4 +
H]+ 363.0873, found 363.0878.
1
7.40 (s, 2H); H NMR (DMSO-d6) δ 1.41 (s, 18 H), 7.70 (s, 2H);
13C NMR (DMSO-d6) δ 28.6, 83.9, 122.5, 149.2, 149.5, 151.3; ESI-
TOF HRMS calcd for [C15H20Cl2N2O4 + H]+ 363.0873, found
363.0876.
4-[(Di-tert-butoxycarbonyl)amino]-2-chloropyridine (2b). 1H
NMR (CDCl3) δ 1.45 (s, 18 H), 7.04 (d, J ) 5.4 Hz, 1H), 7.17 (s,
1H), 8.37 (d, J ) 5.4 Hz, 1H); 13C NMR (CDCl3) δ 27.7, 84.2,
120.7, 122.3, 148.7, 149.9, 150.3, 151.7; ESI-TOF HRMS calcd
for [C15H21ClN2O4 + H]+ 329.1263, found 329.1271.
4-[(Di-tert-butoxycarbonyl)amino]-2-bromopyridine (2c). 1H
NMR (CDCl3) δ 1.45 (s, 18 H), 7.07 (d, J ) 5.2 Hz, 1H), 7.33 (s,
1H), 8.35 (d, J ) 5.2 Hz, 1H); 13C NMR (CDCl3) δ 27.7, 84.2,
121.0, 126.0, 141.9, 148.2, 149.9, 150.3; ESI-TOF HRMS calcd
for [C15H21BrN2O4 + H]+ 373.0757, found 373.0761.
4-[(Di-tert-butoxycarbonyl)amino]-2-tert-butylpyridine (2d).
1H NMR (CDCl3) δ 1.35 (s, 9 H), 1.42 (s, 18 H), 6.90 (d, J ) 5.4
Hz, 1H), 7.10 (s, 1H), 8.54 (d, J ) 5.4 Hz, 1H); 13C NMR (CDCl3)
δ 27.8, 30.0, 37.4, 83.4, 117.8, 119.1, 147.0, 149.1, 150.9, 170.4;
ESI-TOF HRMS calcd for [C19H30N2O4 + H]+ 351.2278, found
351.2282.
3-[(Di-tert-butoxycarbonyl)amino]-2,6-dichloropyridine (7a).
1H NMR (CDCl3) δ 1.41 (s, 18H), 7.30 (d, J ) 8.2 Hz, 1H), 7.51
(d, J ) 8.2 Hz, 1H); 13C NMR (CDCl3) δ 27.7, 84.0, 123.3, 133.2,
140.2, 148.7, 148.7, 149.5; ESI-TOF HRMS calcd for
[C15H21ClN2O4 + H]+ 329.1263, found 329.1268.
3-[(Di-tert-butoxycarbonyl)amino]-2-chloropyridine (7b). 1H
NMR (CDCl3) δ 1.39 (s, 18H), 7.28 (dd, J ) 7.6 and 4.8 Hz, 1H),
7.56 (dd, J ) 7.6 and 1.6 Hz, 1H), 8.35 (dd, J ) 4.8 and 2.0 Hz,
1H); 13C NMR (CDCl3) δ 27.7, 83.6, 122.7, 134.0, 138.1, 148.3,
149.8, 149.8; ESI-TOF HRMS calcd for [C15H21ClN2O4 + H]+
329.1263, found 329.1269.
tert-Butyl 4-(tert-Butoxycarbonylamino)-2-chloronicotinate
(5b). 1H NMR (CDCl3) δ 1.52 (s, 9 H), 1.63 (s, 9 H), 8.20 (d, J )
6.0 Hz, 1H), 8.23 (d, J ) 6.0 Hz, 1H), 8.71 (br s, 1H, NH); 13C
NMR (CDCl3) δ 28.0, 28.0, 82.1, 84.8, 111.7, 115.1, 147.8, 149.9,
150.5, 151.4, 164.9; ESI-TOF HRMS calcd for [C15H21ClN2O4 +
H]+ 329.1263, found 329.1269.
tert-Butyl 4-(tert-Butoxycarbonylamino)-2-bromonicotinate
(5c). 1H NMR (CDCl3) δ 1.52 (s, 9 H), 1.65 (s, 9 H), 8.20 (d, J )
5.0 Hz, 1H), 8.21 (d, J ) 5.0 Hz, 1H); 13C NMR (CDCl3) δ 28.0,
3-[(Di-tert-butoxycarbonyl)amino]-6-chloropyridine (7c). 1H
NMR (CDCl3) δ 1.42 (s, 18H), 7.33 (d, J ) 8.4 Hz, 1H), 7.45 (dd,
J ) 8.4 and 2.8 Hz, 1H), 8.19 (d, J ) 2.8 Hz, 1H); 13C NMR
(10) Herzig, S.; Kritter, S.; Lu¨bbers, T.; Marquardt, N.; Peters, J.-U.; Weber,
S. Synlett 2005, 3107.
J. Org. Chem. Vol. 73, No. 15, 2008 6027

28.0, 82.1, 85.0, 112.0, 118.0, 140.4, 147.0, 150.7, 151.4, 165.1;
ESI-TOF HRMS calcd for [C15H21BrN2O4 + H]+ 373.0757, found
373.0763.
tert-Butyl 4-(tert-Butoxycarbonylamino)-6-chloronicotinate
(6b). 1H NMR (CDCl3) δ 1.54 (s, 9 H), 1.61 (s, 9 H), 8.43 (s, 1H),
8.80 (s, 1H), 10.48 (br s, 1H, NH); 13C NMR (CDCl3) δ 28.1, 28.1,
82.1, 83.7, 110.6, 111.8, 150.0, 151.9, 152.7, 156.3, 166.0; ESI-
TOF HRMS calcd for [C15H21ClN2O4 + H]+ 329.1263, found
329.1272.
8.0 Hz, 1H); 13C NMR (CDCl3) δ 28.1, 81.8, 123.2, 127.0, 132.5,
139.0, 142.5, 152.0; ESI-TOF HRMS calcd for [C10H13ClN2O2 +
H]+ 229.0738, found 229.0739.
tert-Butyl 6-Chloropyridin-3-ylcarbamate (9c). 1H NMR
(CDCl3) δ 1.53 (s, 9 H), 6.73 (br s, 1H, NH), 7.24 (d, J ) 8.8 Hz,
1H), 7.94 (br m, 1H), 8.24 (d, J ) 2.8 Hz, 1H); 13C NMR (CDCl3)
δ 28.0, 81.2, 123.9, 128.7, 134.7, 139.5, 144.1, 152.7; ESI-TOF
HRMS calcd for [C10H13ClN2O2 + H]+ 229.0738, found 229.0741.
Procedure for LDA Treatment of 2a and 10b. To dry THF
(20 mL) under dry N2 cooled to -78 °C with a dry ice-acetone
bath were sequentially added dry diisopropylamine (0.353 mL,
253.0 mg, 2.5 mmol) and then a solution of n-BuLi in hexanes
(2.5 mmol, 0.88 mL, 2.20 mmol) via syringe. After allowing this
mixture to stir at -78 °C for 20 min, a solution of 2a (182.0 mg,
0.5 mmol) and 10b (114.0 mg, 0.5 mmol) in dry THF (3 mL) was
added via syringe. After the reaction mixture was stirred for another
20 min, it was poured into a 25% aqueous solution of NH4Cl (100
mL) followed by addition of EtOAc (80 mL). The biphasic layers
were separated and the aqueous phase was washed with EtOAc (2
× 20 mL). The combined organic phases were washed with a 20%
aqueous solution of Na2CO3 (10 mL) and brine (10 mL), dried over
MgSO4, and evaporated resulting in a residue that was subjected
to chromatography (from hexanes/EtOAc ) 13:1 to 9:1) to afford
5a (170.8 mg, 94%) together with recovery of unreacted 10b (165.6
mg, 91% recovery).
tert-Butyl 4-(tert-Butoxycarbonylamino)-6-bromonicotinate
(6c). 1H NMR (CDCl3) δ 1.53 (s, 9 H), 1.60 (s, 9 H), 8.59 (s, 1H),
8.75 (s, 1H); 13C NMR (CDCl3) δ 28.1, 28.1, 82.1, 83.7, 110.9,
115.6, 147.4, 149.5, 151.8, 152.7, 166.2; ESI-TOF HRMS calcd
for [C15H21BrN2O4 + H]+ 373.0757, found 373.0764.
tert-Butyl 4-(tert-Butoxycarbonylamino)-6-tert-butylnicotinate
1
(6d). H NMR (CDCl3) δ 1.36 (s, 9 H), 1.54 (s, 9 H), 1.58 (s, 9
H), 8.39 (s, 1H), 9.04 (s, 1H); 13C NMR (CDCl3) δ 28.1, 28.2,
29.8, 37.9, 81.2, 82.5, 107.2, 108.9, 148.8, 151.9, 152.3, 166.8,
174.5; ESI-TOF HRMS calcd for [C19H30N2O4 + H]+ 351.2278,
found 351.2284.
Representative Procedure for LDA Treatment of 7: LDA
Treatment of 7a. To dry THF (20 mL) under dry N2 cooled to
-78 °C with a dry ice-acetone bath were sequentially added dry
diisopropylamine (0.21 mL, 152 mg, 1.5 mmol) and a solution of
n-BuLi in hexanes (2.5 M, 1.25 mL, 3.13 mmol) via syringe. After
allowing this mixture to stir at -78 °C for 20 min, a solution of 7a
(181.6 mg, 0.5 mmol) in dry THF (3 mL) was added via syringe.
After the reaction mixture was stirred for another 20 min, it was
poured into a 25% aqueous solution of NH4Cl (100 mL) followed
by addition of EtOAc (80 mL). The biphasic layers were separated
and the aqueous phase was washed with EtOAc (2 × 20 mL). The
combined organic phases were washed with a 20% aqueous solution
of Na2CO3 (10 mL) and brine (10 mL), dried over MgSO4, and
evaporated resulting in a residue that was subjected to chromatog-
raphy (hexanes/EtOAc ) 13:1) to obatin tert-butyl 2,6-dichloro-
pyridin-3-ylcarbamate 9a (64.5 mg, 49% yield). 1H NMR (CDCl3)
δ 1.63 (s, 9 H), 6.95 (br s, 1H, NH), 8.20 (d, J ) 8.8 Hz, 1H), 8.21
(d, J ) 8.8 Hz, 1H); 13C NMR (CDCl3) δ 28.1, 82.1, 123.5, 129.4,
131.7, 137.2, 142.0, 151.8; ESI-TOF HRMS calcd for
[C10H12Cl2N2O2 + H]+ 263.0349, found 263.0349.
Procedure for LDA Treatment of 2b and 10a. A similar
procedure to the one above afforded 5b (149 mg, 91%) and 6b
(6.5 mg, 4%). The unreacted 10a (121.1 mg, 92% recovery) was
also recovered.
Acknowledgment. We are grateful to Prof. William D. Lubell
(University of Montreal) and Drs. Tom Wu, Tetsuo Uno, and
Alex Cortez for their critical reading and helpful suggestions
during the preparation of the manuscript. We also thank Ms.
Tiffany Chuan and Dr. Jae Wook Lee for their assistance in
2D NMR and HRMS analysis.
Supporting Information Available: Characterization of the
synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
tert-Butyl 2-Chloropyridin-3-ylcarbamate (9b). 1H NMR
(CDCl3) δ 1.53 (s, 9 H), 7.00 (br s, 1H, NH), 7.22 (dd, J ) 8.0
and 4.4 Hz, 1H), 8.03 (dd, J ) 4.4 and 1.6 Hz, 1H), 8.49 (d, J )
JO800854D
6028 J. Org. Chem. Vol. 73, No. 15, 2008