Nucleophilic substitution reaction of amines with 3-bromo-4-nitropyridine (and 2-nitropyridine): A new nitro-group migration

Article abstract of DOI:10.3987/COM-05-10455

On the reaction 3-bromo-4-nitropyridine with amine, three in stead of two expected products are separated. 2D NMR spectral data indicate the major product was an unexpected nitro-group migration product. To explore the rearrangement mechanism, a systematic study with various solvents and bases was undertaken. Results obtained indicate that nitro-group migration occurs in polar aprotic solvents; while expected nucleophilic substitution took place under all tested conditions.

Full text of DOI:10.3987/COM-05-10455

HETEROCYCLES, Vol. 65, No. 9, 2005
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HETEROCYCLES, Vol. 65, No. 9, 2005, pp. 2071 - 2081
Received, 23rd May, 2005, Accepted, 25th July, 2005, Published online, 2nd August, 2005
NUCLEOPHILIC SUBSTITUTION REACTION OF AMINES WITH
3-BROMO-4-NITROPYRIDINE (AND 2-NITROPYRIDINE): A NEW
NITRO-GROUP MIGRATION
Jiangchao Yao,* Paul R. Blake, and Ji Yang
Computational, Combinatorial, and Medicinal Chemistry Department Discovery
Research, Purdue Pharma L.P., 6 Cedar Brook Drive, Cranbury, NJ 08512 USA.
E-mail: jiangchao.yao@pharma.com
Abstract – On the reaction 3-bromo-4-nitropyridine with amine, three in stead of
two expected products are separated. 2D NMR spectral data indicate the major
product was an unexpected nitro-group migration product. To explore the
rearrangement mechanism, a systematic study with various solvents and bases was
undertaken. Results obtained indicate that nitro-group migration occurs in polar
aprotic solvents; while expected nucleophilic substitution took place under all
tested conditions.
INTRODUCTION
While undertaking the systematic synthesis of amino-substituted nitropyridines, we separated an
unexpected product, in which the nitro-group migrated from the 4-position to the 3-position. Further
investigations revealed that the 2-nitropyridine could also undergo a migration on the pyridine ring.
Although reactions involving halo-substituted nitropyridines with amines have been described in detail,
and used in the synthesis of biologically active compounds,1-3 nitro-group migration had yet to be reported
for this system, as far as we know. A similar nitro-migration has been described in the reaction of amine
with 4-bromo-5-nitroimidazole4 and 3-bromo-2-nitrobenzothiophene,5 but the reaction proceeds in
different mechanism. In the reaction of nitroimidazole, the migration occurred through the N-dealkylation,
followed by N-realkylation on the other nitrogen. For the reaction of nitrobenzothiophene, the migration
proceeds through a three-member-ring intermediate. The nitro-group migrations have also been reported
on some other aromatic rings under specific conditions: for example, the aromatic nitration,6 the

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HETEROCYCLES, Vol. 65, No. 9, 2005
acid-catalyzed nitroamine rearrangement,7,8 the MeI-catalyzed rearrangement of nitroimidazole,9 the
metabolite of nitroimidazole,10 and the thermal rearrangement of N-nitropyrrazole.11 In order to gain an
understanding of the mechanism behind this rearrangement and improve the product selectivity, we
conducted 17 controlled experiments to explore the effects of temperature, solvent and base on nitro group
migration.
In this paper, we will report the preliminary results of the nitro-group migration and their characterization
by 1 and 2D NMR spectral studies. In order to confirm the substitution geometry identified by the NMR
spectral data, an alternative route for the synthesis of 6 was devised. In addition, we report a convenient
rhenium-catalyzed deoxygenation of nitropyridine N-oxide developed during the course of this study.
N
N
N
N
O-
N+
H
N
N
NO2
Br
NO2
c
a or b
N
N
+
+
+
Br
Br
N
R
NO2
NO2
N
R
N
R
N
R
5 (25%)
4 (14%)
6 (15%)
3a
1
2
O-
nitro-migration
R:
N+
O2N
O
d
e
N
6
1
+
3a
Ph
N
R
7
Scheme 1: Conditions: a, PBr3/CHCl3, rt, 4 h, 11%; b, Re(O)(Ph3P)2Cl3, Ph3P, CH2Cl2, rt, 1 h, then, 40
°C, 2 h, 86%; c, DMSO/TEA, 90 °C, 12 h; d, THF/TEA, 70 °C, 16 h, 83%; e, Re(O)(Ph3P)2Cl3/Ph3P,
CH2Cl2, 45 °C, 2.5 h, 90%.
RESULTS AND DISCUSSION
Preparation of starting material: The starting material (2) has been synthesized from the deoxygenation
of 3-bromo-4-nitropyridine N-oxide (1) (Scheme 1, condition a).12 However, due to the reactivity of the
nitro-group, the literature conditions either give poor yields or complicated mixtures of products13
(MeSO2Cl/TEA,14 ZrCl4/NaBH4,15 LiCl/NaBH4,16 HCO2Na/t-BuCOCl.17).
The recently reported
transition-metal-catalyzed reactions provide an attractive way for the preparation of 2.18, 19 Unfortunately,
the catalysts are not commercially available, and their preparation requires multiple steps to produce.20, 21
We have found that the commercially available rhenium(V)-triphenylphosphine complex catalyzes the
deoxygenation of 1 under mild conditions, affording 2 in 86% yield (Scheme 1, condition b).

HETEROCYCLES, Vol. 65, No. 9, 2005
2073
The nitro-group migration of 4-nitropyridine: When a mixture of 2, 3a, TEA, and DMSO was heated
to 90 °C for 12 h, and purified using flash chromatography, we obtained three products (4, 5 and 6, Scheme
1). Compound (4) has a molecular weight (MW) consistent with nucleophilic substitution of the
nitro-group. Compounds (5) and (6) gave identical MWs, based on MS spectral data, and 1H/13C NMR
spectra consistent with the desired product (6); however, chemical shift and HPLC retention times were
different. Following the logic that products (5) and (6) result from nucleophilic substitution of the
bromo-group, five possible structures can be drawn (Figure 1), which match the observed 1H NMR spectral
patterns. Isomers (9 and 10) were excluded by comparison with the known compounds.22 The remaining
three isomers (5, 6 and 8) were differentiated by 2D 1H -NOESY cross-peak patterns,23 following complete
1H NMR spectral assignments using 2D 1H-COSY,24, 25 –HMQC26 and –HMBC27 spectra: One isomer’s
doublet peak (Ha, 6.90 ppm d, J = 5.9 Hz) has NOE with the Hc (3.30 − 3.34 ppm); the other isomer’s
singlet peak (Hb, 8.63 ppm, s) has NOE with Hd (3.20 − 3.26 ppm).
NO2
NO2
N
N
N
N
NO2
N
N
N
Ha
Hc
NO2
Hb
Hd
NO2
He
Hf
N
N
N
N
R
N
R
N
R
N
R
N
R
5
6
8
9
10
known
known
1
Figure 1: The above five structures would yield H NMR aromatic resonances consistent with the
1
observed H NMR spectrum, one singlet and two doublet. Connections between bold protons on
structures (5) and (6) represent cross peaks observed in 2D NOESY spectra.
In order to confirm the structures of 5 and 6, we decided to make the isomer (6) through a different route.
It has been reported that the reaction of 1 with a nucleophile affords the bromo-substituted product in good
yield,28, 29 so we planned and carried out the reactions (Scheme 1, d and e). The reaction of 3a with 1
exclusively gives the bromo-substituted product (7) in 83% yield; and the rhenium-catalyzed
deoxygenation of 7 affords 6 in 90% yield. LCMS, TLC, 1H NMR, and 13C NMR spectral data confirm
this product is identical to isomer (6).
The nitro-migration of 2-nitropyridine vs 3-nitropyridine. Under the same conditions as the reaction
of 2 with 3a, the reactions of 11 with amines (3a-c) also yielded nitro-migration products (13a-c), in
addition to the expected nucleophilic substitution products (Scheme 2). We characterized the structures
(13a-c) of the nitro-group migration products by synthesizing 13a-c via a different route (Scheme 2).30, 31
As shown in Scheme 2, the isolated yields of the nitro-migration product vary between amines: the reaction
of benzylamine (3c) gives 13c (30%) as the major product; while, the reaction of piperidine (3b) affords

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HETEROCYCLES, Vol. 65, No. 9, 2005
13b (14%) as a minor product. We also compared the reaction of 3-chloro-2-nitropyridine (15) and
2-chloro-3-nitropyridine (17) with 3b (Table 1, Reactions 4 and 5). The reaction of 15 with 3b yields the
nitro-migration product (13b) in addition to the nitro- and chloro-substituted products (16 and 14b). On
the other hand, there is no nitro-migration in the reaction of 17 with 3b under the same conditions
(DMSO/TEA) or the literature conditions (Scheme 2, TEA/MeCN);33 in these cases only the
halo-substituted product (13b) is observed.
R
X
NO2
R
DMSO/TEA
90 0C, 4 h
X
R
+
+
3a-c
+
NO2
NO2
N
N
N
N
12a-c X =Br
16 X = Cl
11 X = Br
15 X = Cl
14a-c
13a-c
nitro-migration
NO2
MeCN/TEA
70 0C, 24 h
13a (80%), 13b (92%) or 13c (96%)
+ 3a-c
N
Cl
17
Scheme 2: The comparision of 2-nitropyridine vs 3-nitropyridine (for detail, see Table 1)
Table 1: The reaction results of 2-nitropyridine and 3-nitropyridine
Reaction Starting material
R
Product, yield (%)a
N
N
1
11
3a
12a (20) 13a (23)
14a (15)
O
N
2
11
3b
12b (19) 13b (14)
14b (17)
14c (5)
3
4
11
15
3c
3b
C6H5CH2NH 12c (18) 13c (30)
N
16 (58)b 13b (18)b 14b (24)b
N
13b (100)b
5
17
3b
a Isolated yield; b 1H NMR spectral yield.
In order to understand what factors contribute to nitro-group migration in this system, we performed 17
controlled experiments to examine the effects of: (i) starting material ratios, (ii) temperature, and (iii)
solvents and bases, on product selectivity. 1H NMR spectra of starting material (11), and the three
products (12b, 13b, and 14b) can be clearly identified in the aromatic region (Figure 2). The 17 controlled
reaction mixtures are analyzed by 1HNMR spectroscopy and are summarized in Table 2. The nucleophilic

HETEROCYCLES, Vol. 65, No. 9, 2005
2075
substitution products (12b and 14b) are formed under all of the tested conditions, while the nitro-migration
only occurs in polar aprotic solvent. The best condition for nitro-migration product (13b, 31%) is the
reaction of 15 in N-methyl-2-pyrrolidinone (NMP).
In non-polar solvents or protic
1
Figure 2: Part of the aromatic region of the H NMR (CDCl3) spectra for two crude reaction
mixtures (15 and 17), starting material (11), and three purificed products (12b, 13b and 14b). Gray
vertical lines associate proton resonances for know purified products with those in the crude reaction
mixures. As depicted, the unique chemical shifts and coupling patterens for the known purified
compounds afforded complete analysis of the crude reation mixtures.
solvents, the nitro-migration is completely inhibited (Reaction 10, 11 and 16), the yield of 13b is 0%. In a
strong polar aprotic solvent (DMF, DMSO, or DMP), the yield of 13b varies from 22% to 31%. In
addition to solvent, base also plays a pivotal role in nitro-migration. The use of excess TEA (1.0 eq., 2.0 eq.
vs 4.0 eq.) increases the yield of 13b from 17% to 22%. When increasing amounts of amine 3b (1.0 eq.,
2.0 eq. vs 3.0 eq.), in the presence of a base, the yield of nitro-migration product (13b) drops from 22% to
3% (Reactions 3, 4 and 5). In the absence of a base (Reaction 6, 2.0 eq. of amine 3b), the yield of 13b
decreases to 2%. These various reaction conditions clearly indicate that excess amine inhibits

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HETEROCYCLES, Vol. 65, No. 9, 2005
nitro-migration. Increasing the reaction temperature (50 °C, 70 °C vs 90 °C) provides higher yields of 13b
from 14% to 22% (Reactions 3, 7 and 8); however, the reaction mixture becomes too complicated to
interpret above 100 °C.
Table 2: The effects of solvent, temperature, and basea
Temp (°C)
Time(h)
90, 5
12b, 13b,
14b (%)d
3b/11b
Solvent
Base (eq) b
11 (%)c
Reaction
1
2
1
1
1
2
3
2
1
1
1
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
TEA (1)
TEA (2)
TEA (4)
TEA (4)
TEA (4)
74
80
43, 17, 43
43, 17, 43
43, 22, 35
50, 10, 40
54, 3, 43
48, 2, 48
48, 14, 38
45, 18, 37
45, 18, 37
62, 0, 38
90, 5
3
90, 5
90
4
90, 5
95
5
90, 5
100
100
80
e
6
─
90, 5
7
TEA (4)
TEA (4)
TEA (4)
TEA (4)
50, 15
70, 15
90, 5
8
90
9
97
10
i-PrOH
90, 5
69
O
11
1
TEA (4)
90, 5
62
66, 0, 34
O
12
13
14
1
1
1
MeCN
DMSO
DMSO
TEA (4)
DIPEA (4)
K2CO3 (4)
90, 5
90, 5
90, 5
90
80
50, 5, 25
42, 25, 33
42, 16, 42
100
O
N
15
1
K2CO3 (4)
K2CO3 (4)
80, 12
100
38, 31, 31
16
17
2
2
Toluene
80, 12
80, 12
100
41
77, 0, 23
43, 0, 57
ClCH2CH2Cl K2CO3 (4)
a, All reactions were performed on the same scale: 0.1 mmol of 11, and 0.5 mL of solvent; b,
the mole ratio to 11; c, conversion of 11; d, 1H NMR spectral yield; e, no base, two eq. of 3b.
As for the reaction mechanism, we believe that 12a-c and 14a-c are formed through classic nucleophilic
substitution (SNAr) 32 as shown in Scheme 3. The intermediates proposed by Spinelli et al.33, 34 can explain
the formation of 13a-c and the solvent effects (Scheme 3). The key step for nitro-group migration is the
addition of a second amine to 19, forming intermediate (20). Intermediate (19) is a reactive dipolar
molecule and will eliminate bromo to produce 14a-c. However, the polar aprotic solvents (DMF, DMSO)
have dual roles in accelerating the formation of 20: Stabilizing intermediate (19), and increasing the
nucleophilic reactivity of the amine.35 Once intermediate (20) is formed, it undergoes a cyclization to form

HETEROCYCLES, Vol. 65, No. 9, 2005
2077
21, relieving the two negative charges on the nitro-group. The aza induction makes intermediate (22)
more stable than 21, resulting in the elimination of amine (22) and yielding 13a-c.
SUMMARY
In summary, we have reported a novel nitro-group migration on the pyridine ring. The nitro-migration
only occurs with substrates of 2- or 4-nitropyridines (not 3-nitropyridine), and only occurs in polar aprotic
solvents. We also reported a convenient deoxygenation condition for the nitropyridine N-oxide.
H+
R2
R1
R2
Br
R1
N
N
Br
Br
- BH
Br
-NO2-
-Br-
- BH
11 + 3
12a-c
14a-c
O–
NO2
NO2
O–
N
N+
O–
N
N
N
N+
O–
NH+R1R2
NR1R2
19
18
23
24
R2
R1
R1
R2
R1
R2
R1
R2
NH+
N
N
N
O–
-R1R2NH
Br
O–
Br
+ R1R2NH
- Br-
O–
O–
N+
O–
13a-c
N+
O–
O–
N
- R1R2NH
N
N
N
N
N+
O–
N
N+H
R2
NH+
R2
R1
R1
R1
R2
R1
NH
R2
19
20
21
22
Scheme 3: The mechanism for 12, 13, and 14
EXPERIMENTAL
All commercially available solvents and reagents were used as received. NMR spectra
were obtained at 400 MHz on a Brucker AVANCE400 spectrometer. Chemical shifts are
reported in ppm downfield from TMS as an internal standard. Flash chromatography was
done using EM science silical gel 60 (230-400 mesh). TLC was performed on Analtech silica
gel GF pre-scored plates (250 μm). MS spectra and HPLC analysis was carried on Agilent
1100 Series LC/MSD equipment. Melting points were determined in open capillaries on
Gallenkamp electrothermal apparatus.
3-Bromo-4-nitropyridine (2, condition b).
A mixture of 1 (2.2 g, 10 mmol),
trichlorooxobis(triphenylphosphine)rhenium(V) [Re(O)(Ph3P)2Cl3, Aldrich, 50 mg, 0.08
mmol), and triphenyphosphine (2.7 g, 10.3 mmol) in dichloromethane (100 mL) was flushed
with argon, and stirred at rt for 1 h, then, at 40 °C for 2 h. The reaction mixture was cooled
to rt, and concentrated under vacuum. The residue was triturated with hexanes (300 mL),
and the precipitated (triphenylphosphine oxide) was removed by filtration. The organic
layer was concentrated, and purified by column (silica gel, EtOAc/hexanes 1/7) to give 2 as

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HETEROCYCLES, Vol. 65, No. 9, 2005
yellow solid (1.8 g, 86%).
3-Phenyl-1-piperazin-1-ylpropynone (3a). To a solution of phenylpropynoic acid (10 g, 68
mmol), 1-hydroxybenzotriazole (HOBt, 1.0 g, 7 mmol), and piperazine-1-carboxylic acid
tert-butyl ester (12 g, 63 mmol) in CH2Cl2 (200 mL) was added 1,3-diisopropylcarbodiimide
(DIC, 11 mL, 70 mmol) over 15 min at 0 °C. After 30 min at 0 °C, the reaction was allowed
to warm to rt in a period of 18 h. The reaction mixture was cooled with ice water, and the
white solid was removed by filtration. The organic layer was washed with NaOH (2N aq
solution, 80 mL), water (30 mL), and brine (30 mL). The solvent was removed under
vacuum to afford Boc-protected 3a. To a solution of BOC-protected 3a in 30 mL of
1,4-dioxane was added 4 mL of HCl (4N solution in 1,4-dioxane, 16 mmol) at 0 °C. The
reaction mixture was heated to 50 °C for 24 h. The solvent was removed under vacuum.
The residue was washed with Et2O (4x20 mL) to afford 3a as HCl-salt (white solid, 1.3 g,
81%, mp 186 − 188 °C,). 1H NMR (CD3OD) δ 7.64 − 7.66 (m, 2H), 7.44 − 7.55 (m, 3H), 4.16 −
4.19 (m, 2H), 3.93 − 3.96 (m, 2H), 3.38 − 3.41 (m, 2H), 3.29 − 3.32 (m, 2H). Anal. Calcd for
C13H15N2OCl: C, 62.28; H, 6.03; N, 11.17. Found: C, 62.54; H, 5.74; N, 11.09.
General procedure for the preparation of 4, 5, 6, 12a, 13a, and 14a: A mixture of
nitropyridine (2 or 11, 203 mg, 1.0 mmol), 3a (214 mg, 1.0 mmol), TEA (0.4 mL, 2.8 mmol)
and DMSO (2 mL) was heated to 90 °C for 12 h. The reaction mixture was cooled to rt,
diluted with ethyl acetate (10 mL), and washed with water (2x5 mL). The organic layer
was separated, concentrated under vacuum, and the residue was purified by column (silica
gel, CH2Cl2/THF v/v, 20/3) to give the desired products.
1-[4-(3-Bromopyridin-4-yl)piperazin-1-yl]-3-phenylpropynone (4). Colorless oil, 14% yield.
TLC (CH2Cl2/THF, 20/3, Rf 0.5). 1H NMR (CDCl3) δ 8.62 (s, 1H), 8.40 (d, J = 5.5, 1H), 7.55 −
7.58 (m, 2H), 7.36 − 7.46 (m, 3H), 6.83 (d, J = 5.5, 1H), 4.03 − 4.06 (m, 2H), 3.89 − 3.92 (m,
2H), 3.26 − 3.29 (m, 2H), 3.19 − 3.22 (m, 2H); MS (m/z): 370 (M + H). Anal. Calcd for
C18H16N3OBr: C, 58.39; H, 4.36; N, 11.35. Found: C, 57.99; H, 4.21; N, 11.02.
1-[4-(3-Nitropyridin-4-yl)piperazin-1-yl]-3-phenylpropynone (5). Yellow solid (mp 148 −
149 °C, 25%). TLC (CH2Cl2/THF, 20/3, Rf 0.3). 1HNMR (CDCl3) δ 8.94 (s, 1H), 8.48 (d, J =
5.8, 1H), 7.57 − 7.59 (m, 2H), 7.39 − 7.46 (m, 3H), 6.92 (d, J = 6.0, 1H), 4.05 − 4.08 (m, 2H),
3.90 − 3.93 (m, 2H), 3.32 − 3.35 (m, 4H); 13C NMR (CDCl3) δ 153.7, 150.1, 148.7, 137.1, 132.8,
130.7, 129.0, 120.4, 113.3, 92.0, 80.9, 50.6, 49.3, 46.5, 41.2; MS (m/z): 336 (M + H), 359 (M +
23); Anal. Calcd for C18H16N4O3: C, 64.28; H, 4.79; N, 16.66. Found: C, 64.62; H, 4.52; N,
16.45.

HETEROCYCLES, Vol. 65, No. 9, 2005
2079
1-[4-(4-Nitropyridin-3-yl)piperazin-1-yl]-3-phenylpropynone (6). Orange solid (mp 145 −
146 °C, 15%). TLC (CH2Cl2/THF, 20/3, Rf 0.6). 1HNMR (CDCl3) δ 8.62 (s, 1H), 8.47 (d, J =
5.3, 1H), 7.60 (d, J = 5.7, 1H), 7.55 − 7.58 (m, 2H), 7.36 − 7.46 (m, 3H), 4.01 − 4.04 (m, 2H),
3.87 − 3.90 (m, 2H), 3.23 − 3.26 (m, 2H), 3.19 − 3.22 (m, 2H); 13C NMR (CDCl3) δ 153.6, 148.5,
145.8, 145.1, 139.4, 132.8, 130.7, 129.0, 120.6, 118.1, 91.8, 81.1, 52.4, 51.5, 47.4, 41.8; MS
(m/z): 336 (M + H), 359 (M + 23); Anal. Calcd for C18H16N4O3: C, 64.28; H, 4.79; N, 16.66.
Found: C, 64.8; H, 4.51; N, 16.21.
1-[4-(3-Bromopyridin-2-yl)piperazin-1-yl]-3-phenylpropynone (12a). White solid (mp 105 −
106 °C, 20%). TLC (EtOAc/hexanes, 7/3, Rf 0.72); 1HNMR (CDCl3) δ 8.25 (dd, J = 1.7, 4.8,
1H), 7.82 (dd, J = 1.5, 7.8, 1H), 7.55 − 7.58 (m, 2H), 7.36 − 7.45 (m, 3H), 6.84 (dd, J = 4.6, 7.7,
13
1H), 4.00 − 4.03 (m, 2H), 3.86 − 3.89 (m, 2H), 3.41 − 3.43 (m, 2H), 3.34 − 3.37 (m, 2H); C
NMR (CDCl3) δ 159.4, 153.7, 146.9, 142.8, 132.8, 130.5, 128.9, 120.8, 119.7, 113.5, 91.3, 80.5,
50.2, 49.7, 47.4, 41.9; MS (m/z): 371 (M + H); Anal. Calcd for C18H16N3OBr: C, 58.39; H, 4.36;
N, 11.35. Found: C, 58.47; H, 3.96; N, 10.97.
1-[4-(3-Nitropyridin-2-yl)piperazin-1-yl]-3-phenylpropynone (13a). Yellow solid (mp 156 −
158 °C, 23%). TLC (EtOAc/hexanes, 7/3, Rf 0.38); 1H NMR (CDCl3) δ 8.41 (dd, J = 1.7, 4.6,
1H), 8.22 (dd, J = 1.7, 7.9, 1H), 7.58 − 7.61 (m, 2H), 7.39 − 7.46 (m, 3H), 6.88 (dd, J = 4.7, 8.1,
1H), 4.01 − 4.04 (m, 2H), 3.86 − 3.88 (m, 2H), 3.53 − 3.58 (m, 4H); 13C NMR (CDCl3) δ 153.7,
153.1, 152.4, 136.1, 133.9, 132.8, 130.7, 128.9, 120.6, 115.1, 91.6, 81.2, 48.9, 48.1, 46.9, 41.6;
MS (m/z): 337 (M + H); Anal. Calcd for C18H16N4O3: C, 64.28; H, 4.79; N, 16.66. Found: C,
64.06; H, 4.75; N, 16.23.
1-[4-(2-Nitropyridin-3-yl)piperazin-1-yl]-3-phenylpropynone (14a). Yellow solid (mp 120 −
123 °C, 15%). TLC (EtOAc/hexanes, 7/3, Rf 0.12); 1H NMR (CDCl3) δ 8.21 (dd, J = 1.5, 4.4,
1H), 7.64 (dd, J = 1.5, 8.1, 1H), 7.55 − 7.58 (m, 2H), 7.53 (dd, J = 4.6, 8.1, 1H), 7.36 − 7.46 (m,
3H), 3.97 − 4.01 (m, 2H), 3.84 − 3.87 (m, 2H), 3.10 − 3.15 (m, 4H); 13C NMR (CDCl3) δ 153.7,
153.6, 142.7, 140.3, 132.8, 132.0, 130.7, 129.0, 128.6, 120.5, 91.7, 81.1, 52.5, 51.3, 47.3, 41.8;
MS (m/z): 337 (M + H); Anal. Calcd for C, 64.28; H, 4.79; N, 16.66; Found: C, 64.30; H, 4.72;
N, 16.63.
Alternative route for the synthesis of 6: To a suspended solution of 1 (2.0 g, 9.1 mmol) and
TEA (10 mL, 70 mmol) in 120 mL of THF was added amine (3) (2.0 g, 9.3 mmol). The reaction
mixture was heated and stirred at 70 °C for 16 h under argon. After cooling to rt, the
reaction mixture was diluted with dichloromethane (200 mL), then washed with water (20
mL) and brine (20 mL). The organic layer was dried (Na2SO4), concentrated under vacuum

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and purified by column (silica gel, EtOAc) to give intermediate (7) as yellow solid (2.6 g,
83%). To a solution of 7 (500 mg, 1.4 mmol) in dichloromethane (20 mL) was added
triphenylphosphine (450 mg, 1.7 mmol) under argon. The reaction mixture was flushed with
argon, then, the catalyst Rh(O)(Ph3P)2Cl3 (70 mg, 0.08 mmol) was added in one portion.
After heating at 45 °C for 2.5 h under argon, the reaction mixture was cooled to rt, the
solvent was removed under vacuum, and purified by column (silica gel, MeOH/CH2Cl2 2/100)
to obtain 6 as yellow solid (0.45 g, yield, 95%).
ACKNOWLEDGEMENT
The authors would like to thank Dr. R. Richard Goehring and Dr. Parviz Gharagozloo for helpful
discussion, and Mr. John Engel for reviewing the manuscript.
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