Approach to vicinal t-Boc-amino dibromides via catalytic aminobromination of nitrostyrenes without using chromatography and recrystallization

Article abstract of DOI:10.1021/jo302727v

A 1.0 mol % amount of K₃PO₄·3H₂O was found to catalyze aminohalogenation reaction of nitrostyrenes with N,N-dibromo-tert-butylcarbamate (t-Boc-NBr₂) in a dichloroethane system. Good to excellent yields and compl

Full text of DOI:10.1021/jo302727v

Article
pubs.acs.org/joc
Approach to Vicinal t‑Boc-amino Dibromides via Catalytic
Aminobromination of Nitrostyrenes without Using Chromatography
and Recrystallization
Hao Sun,†,‡ Jianlin Han,†,‡ Padmanabha V. Kattamuri,§ Yi Pan,*,†,‡ and Guigen Li*,‡,§
‡
†School of Chemistry and Chemical Engineering and Institute of Chemistry & BioMedical Sciences, Nanjing University, Nanjing
210093, P. R. China
§Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
S
* Supporting Information
ABSTRACT: A 1.0 mol % amount of K3PO4·3H2O was
found to catalyze aminohalogenation reaction of nitrostyrenes
with N,N-dibromo-tert-butylcarbamate (t-Boc-NBr2) in a
dichloroethane system. Good to excellent yields and complete
regioselectivity have been achieved by taking advantage of the
GAP workup without using traditional purification techniques such as column chromatography and recrystallization. A new
mechanism is proposed involving radical and ionic catalytic cycles and an intramolecular migration.
adequate solubility; i.e., the products must be dissolved some
solvents (e.g., THF, DCM, etc.) for further transformations but
should not be readily dissolved in others (e.g., hexane,
petroleum ether, their mixtures with EtOAc, etc.); the
functional groups should enable their attached substrates to
have efficient chemical reactivity toward various species; For
asymmetric reactions, the functional groups should be able to
show efficient asymmetric induction and control; the functional
groups should have great flexibility for structural modifications
so that both physical (e.g., solubility) and chemical properties
(tolerable to further transformations) of resulting products can
be readily adjusted; the functional group-attached auxiliaries
can be cleavable under various conditions and recycled for
reuse. So far, controlling solubility of organic products via
designing auxiliaries has been very challenging in chemical
synthesis. The N-phosphonyl and N-phosphinyl functional
group-based GAP chemistry has been proven to meet this
purpose due to the special polarity of PO bonds in which
adequate amount of negative charge and positive charge
localized on oxygen and phosphorus, respectively. We are
pleased to find that this concept can be extended to other
reactions such as aminohalognation of olefins as shown in this
paper.
INTRODUCTION
■
The aminohalogenation reaction has become an important tool
for the synthesis of vicinal haloamine compounds that are
versatile building blocks in organic and medicinal chemistry.1−6
For example, they can be readily converted into many other
synthetic precursors, such as aziridines and enamines. In the
past one decade, many efforts have been devoted to this
reaction under a series of metal-catalyzed and organocatalytic
conditions. Functionalized substrates, such as α,β-unsaturated
carboxylic esters,4,5 α,β-unsaturated nitriles,7 α,β-unsaturated
ketones,8 β-nitrostyrenes,9 and other substrates,5,10 have been
proven to be suitable for the aminohalogenation reaction. In
the meantime, several nitrogen/halogen sources including N,N-
dichlorotoluenesulfonamide (TsNCl2),4,5 NsNCl2/NsNHNa,4
N-bromoacetamide,11 chloramine-T,11 p-TsNH2/NBS,12
NsNCl2/NsNH2,13 and tert-butyl-N,N-dibromo- and dichlor-
ocarbamates14 have been found to be efficient for amino-
halogenation reaction with very well controlled regio- and
stereoselectivity. The reaction is believed to go through the
formation of aziridinium intermediates, halonium (bromonium
or chloronium) intermediates, or radicals. An aziridinium
intermediate-based mechanism has been confirmed by the
direct formation of imidazoline products that serve as a new
protocol for the synthesis of diamino compounds.1b,14
Very recently, we established a new concept called the GAP
chemistry (group-assistant-purification chemistry). This chem-
istry can avoid the use of traditional purification methods such
as chromatography or recrystallization, and the pure products
can be obtained simply by washing the solid crude products
with organic solvents.15−17 This new concept is attributed to
the discovery of achiral/chiral N-phosphonyl and chiral N-
phosphinylimine reagents and their reactions. The character-
istics of GAP chemistry require that the functional groups of
starting materials should enable the resulting products to have
RESULTS AND DISCUSSION
■
The present aminobromination reaction is based on the use of
β-nitrostyrenes as the substrates due to their high flexibility for
further transformations. The reaction was performed in 1,2-
dichloroethane at room temperature without using inert gas
protection (Scheme 1). The loading of 1.0 mol % of
K3PO4·3H2O was able to efficiently catalyze the reaction to
Received: December 16, 2012
Published: January 11, 2013
© 2013 American Chemical Society
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Article
carbonate with KOH to give a quantitative yield. Essentially,
there is no need for further purification of the crude tert-butyl
N,N-dibromocarbamate after workup was performed; it was
directly subjected to the aminobromination reaction with
nitrostyrene. It should be pointed out that as compared with
the known procedure by Zwierzak and co-workers in which
crude product was contaminated with about 9% of tert-butyl N
bromocarbamate, the present modification would provide an
alternative and more efficient approach to tert-butyl-N,N-
dibromocarbamate on a large scale. In addition, this synthesis
belongs to our GAP chemistry in which the products were
purified without using chromatography and recrystallization.
After the catalytic system was established, we investigated the
substrate scope of this aminobromination reaction by using a
variety of nitrostyrene derivatives with substituents on their
aromatic rings. As shown in Table 1, this reaction showed a
Scheme 1
completion within 1 h, affording vicinal bromoamine products
in good to excellent yields (up to 99%). Since several polar
functional groups, nitro, t-Boc, and two bromo moieties, exist in
the structures of resulting products, they can lower the
solubility of product in organic solvents and enable GAP
purification to be performed. Small amounts of impurities are
either dissolved in alcohol or washed away simply by washing
with some organic solvents.
At the beginning of our study, we performed the reaction
according to the literature procedure.13 As anticipated, since
nitrostyrene is a difficult aminobromination substrate, it did not
result in any products when it was subjected to reaction with
tert-butyl N,N-dibromocarbamate for up to 16 h in dichloro-
methane at room temperature. Screening of a series of organic
bases, inorganic bases, and salts was carried out, including
several organic bases: DMAP, DIPEA, triethylamine, and
triphenylphosphine. We found that these common organic
bases afforded no or trace amounts of products as monitored by
TLC. Inorganic salts such as sodium fluoride, NaOAc, KHCO3,
NaHCO3, and K2HPO4 were also proven to be ineffective,
giving no product either. Na2CO3, K2CO3, anhydrous
Na3PO4,13 and Ca(OH)2 (10 mol %) resulted in less than
49% of vicinal aminobromides within 1 h as monitored by TLC
determination. Two stronger bases, sodium and potassium
hydroxide, gave good yields of 86% and 81%, respectively.
Table 1. K3PO4·3H2O-Catalyzed Aminobromination of
a
Nitrostyrenes
b
entry
Ar
product
yield (%)
1
Ph
3a
3b
3c
3d
3e
3f
98
98
94
99
95
91
97
91
82
95
92
88
99
96
98
86
88
98
98
83
2
4-ClC6H4
3
4-MeOC6H4
2-ClC6H4
4
5
4-MeC6H4
6
4-CF3C6H4
4-CNC6H4
2-naphthyl
7
3g
3h
3i
18
8
Pleasantly, when anhydrous K3PO4 and K3PO4·3H2O were
9
1-naphthyl
employed as the catalyst, more than 90% chemical yield was
achieved under the same conditions; similar results were
obtained by decreasing the catalyst loading to 5.0 and 2.5 mol
%, respectively. The above reaction was performed by reacting
1.0 mmol of nitrostyrene with 1.2 mmol of tert-butyl N,N-
dibromocarbamate in 2.5 mL of dichloromethane at room
temperature. However, when the catalyst loading was decreased
to 1.0 mol %, no product was observed. However, then the
volume of solvent was changed from 2.5 to 1.0 mL, > 90% of
chemical yield was obtained.
10
11
12
13
14
15
16
17
18
19
20
2-BnOC6H4
2, 6-Cl2C6H3
3, 4-Cl2C6H3
4-FC6H4
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
4-BrC6H4
3-FC6H4
3-BrC6H4
3-Br-4-MeOC6H3
2-MeOC6H4
3, 4-(CH3O)2C6H3
4-butyl-C6H4
To explore further improvements, we next examined a series
of solvents. Three solvents, ethyl acetate, acetonitrile, and
acetone, gave very poor yields (5−37%); three other solvents,
THF, DMF, and ethanol, did not show any products. However,
1,2-dichloroethane was found to be even more effective and
resulted in an almost quantitative yield when the reaction was
performed by using 1.2 equiv of tert-butyl N,N-dibromocarba-
mate in the presence 1.0 mol % of K3PO4·3H2O in 1.0 mL of
solvent within 1 h. The actual loading of K3PO4 is lower than
1.0 mol % if water is excluded from the above stoichiometric
calculation.
Since K3PO4·3H2O was used in a tiny amount (1.0 mol %),
after it was added into reaction mixture containing tert-butyl
N,N-dibromocarbamate and nitrostyrene in 1,2-dichloroethane,
it could be easily dissolved. At the beginning, the color of
reaction mixture was yellow; it gradually became light greenish
as the reaction proceeded for 20−30 min.
The preparation of tert-butyl N,N-dibromocarbamate was
performed by following the literature procedure.13 In its
synthesis, a modification was made by replacing potassium
a
Conditions: 1a (1.0 mmol), BocNBr2 (1.2 mmol), with K3PO4·3H2O
(0.01 mmol) in (CH2Cl)2 (1 mL) at room temperature for 60 min.
b
Isolated yields.
great substrate scope in which 20 substrates were proven to be
suitable for this system. There is no particular trend for these
substrates. Most electron withdrawing group (EWG) attached
substrates gave nearly quantitatively chemical yields (entries 2,
4, 7, 13, and 15, Table 1); only 4-CF3 and two dichloro-
substituted substrates (entries 6, 11, and 12, Table 1) gave
slightly lower yields of 91%, 92%, and 88%, respectively.
Interestingly, strong electron donating group (EDG) attached
substrates usually give lower chemical yields as compared with
those with neutral and EWG-attached substrates, but in this
catalytic system, 2-MeO-Ph and 3,4-(MeO)2-Ph cases also
afforded the vicinal aminobromide products in quantitatively
yields (entries 18 and 19, Table 1). Two other EDG cases, 4-
MeO-Ph and 2-BnO-Ph, also showed excellent yields of 94%
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and 95%, respectively (entries 3 and10, Table 1). There are no
side products generated from bromination on phenyl rings
observed as at all. It is not clear why two neutral cases, 1-
naphthyl and 4-butyl-Ph (entries 9 and 20, Table 1), resulted in
lowest chemical yields of 82% and 83%, respectively.
As mentioned that this reaction resulted in vicinal amino-
bromide products which can be purified via GAP process
without the use of traditional column chromatography and
recrystallization, i.e., after workup is done, the pure product can
be readily obtained simply by washing the crude product with
organic solvents (in this case, hexane). We also conducted the
reaction of nitrostyrene on a scale of 3.0 g (20 mmol) and
obtained product 1b in almost quantitative yield (Scheme 2),
which indicates that the present reaction is promising for large-
scale production.
It should be noted that the present work represents the first
GAP chemistry example of nonimine-based reactions in our
laboratories. It can encourage synthetic chemists to find more
GAP preparations so as to reduce the consumption of organic
solvents and silica gels for column chromatography. Therefore,
the use of nature’s energy resources and manpower can be
minimized due to the fast synthesis GAP chemistry. If GAP is
employed for pharmaceutical and industrial productions on
large scales, the environmentally contaminations can also be
reduced substantially.
In conclusion, we have demonstrated a concise and efficient
aminobromination of β-nitrostyrene derivatives with N,N-
dibromocarbamate as nitrogen/bromine sources in the
presence of 1.0 mol % of K3PO4·3H2O as catalyst. This
reaction proceeded smoothly and environmentally friendly to
give the β,β-dibromo Boc-protected amines in complete
regioselectivity and good to excellent yields (82−99%). By
using 1.2 equiv of nitrogen/bromine sources, the reaction can
occur to completion within 1 h at room temperature without
using protection of inert gases. The GAP chemistry was found
to be suitable for simple purifying the products without using
traditional purification techniques of column chromatography
and recrystallization. A mechanism involving spontaneously
initiated free-radical chain and ionic catalytic cycles was
proposed to account for experimental observations. Finally,
this reaction showed promising result for practical scale up
synthesis.
Scheme 2
The vicinal aminobromide products have been fully
determined by NMR spectroscopic, HR-MS analysis, etc., and
the product of 3a has been unambiguously analyzed by X-ray
diffractional analysis with the ORTEP diagram presented in
Figure 1 (see the Supporting Information).
This reaction is suggested to proceed through the free-radical
chain stage and ionic catalytic cycle (Scheme 3). The first stage
EXPERIMENTAL SECTION
■
General Methods. Commercial chemicals and solvents were used
without any further purification. Melting points were uncorrected. IR
spectra were collected in KBr pellets. 1H NMR, 13C NMR (TMS used
as internal standard) spectra were collected in CDCl3. High-resolution
mass spectra for all the new compounds were collected on a Q-TOF
instrument (Supporting Information).
Scheme 3
Procedure for Preparation of BocNBr2. To a stirred solution of
BocNH2 (5.86 g, 50 mmol) and NaOH (4.0 g, 0.1 mol) in water (50
mL) was added bromine Br2 (19 g, 0.12 mol) dropwise at room
temperature and the solution stirred for another 2 h. When the
reaction was complete, a large amount of orange solid was formed,
which was filtered to get the crude product. The residue was dissolved
in CH2Cl2, washed with brine, dried with anhydrous Na2SO4, and
concentrated to obtain the pure product (13.7g, quant). Mp = 93−94
°C (lit.13a mp 93−95 °C). H NMR (300 MHz, CDCl3): δ 1.49 (s,
1
9H).
Typical Procedure for the Aminobromination Reaction. Into a
vial were added 1a (149 mg, 1 mmol), BocNBr2 (330 mg, 1.2 mol),
K3PO4·3H2O (2.7 mg, 1 mol %), and (CH2Cl)2 (1.0 mL) and the
misture stirred for 60 min at room temperature. The reaction
completion was indicated by TLC and the color change, which turned
from yellow to light green. The reaction mixture was washed with
brine and the aqueous phase extracted with DCM. The organic layer
was dried with anhydrous Na2SO4 and concentrated to near-dryness to
give a solid/oil mixture. A tiny amount of oil was washed away by
hexane; if more oil stuck on solid product appeared, 10 mL of hexane
was added into the above mixture which was heated to give a solution
mixture containing white solids. After being cooled to room
temperature, the solution was filtrated off to afford pure product 3a.
1-(tert-Butoxyformamido)-2,2-dibromo-1-phenyl-2-nitroethane
of the radical mechanism has been proposed for the reaction of
t-Boc-NBr2 with styrene in the literature.13 This catalytic cycle
involves the common spontaneous initiation, propagation, and
radical termination to generate the monobromide intermediate
3−
(A). The deprotonation of A by PO4 leads to the formation
of intermediate B and P(OH)O32−. The intramolecular
migration of bromine from amide nitrogen onto carboanion
to give intermediate C in which the negative charge can be
shifted onto the oxygen of the t-Boc group. Two contributing
structures exist for this negative charge shifting. The
−
protonation of C by P(OH)O3 affords the final product 3a
and concurrently gives the catalytic species, PO43−, back for
continuing cycles of stage 2. This mechanistic hypothesis can
account for the following observations: (1) several common
bases, such as KOH, NaOH, Ca(OH)2, K2CO3, etc., can also
serve as the catalysts for this reaction, although they are not as
efficient as K3PO4; (2) only 1.2 equv of t-Boc-NBr2 (no need
for 2.0 equiv) is needed for the complete consumption of the
starting material of nitrostyrene.
1
(3a): white solid (415 mg, 98%). Mp = 122−124 °C. H NMR (300
MHz, CDCl3): δ 7.45−7.35 (m, 5H), 5.97 (d, J = 10.20 Hz, 1H), 5.60
(d, J = 9.60 Hz, 1H), 1.44 (s, 9H) ppm. 13C NMR (75.45 MHz,
CDCl3): δ 153.8, 133.5, 129.4, 129.0 (2), 128.4 (2), 94.5, 81.1, 64.4,
28.0 (3) ppm. IR (KBr): ν = 3313, 2976, 1693, 1572, 1520, 1456,
1367, 1319, 1248, 1167, 837, 700 cm−1. MS (ESMS/[M + Na]+):
calcd for C13H16Br2N2O4Na 446.9349, found 446.9331.
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1-(tert-Butoxyformamido)-2,2-dibromo-1-(4-chlorophenyl)-2-ni-
(KBr): ν = 3240, 3134, 2977, 1693, 1577, 1361, 1257, 1159, 1049, 775
cm−1.
1
troethane (3b). White solid (449 mg, 98%). Mp = 121−123 °C. H
NMR (300 MHz, CDCl3): δ 7.39 (d, J = 9.00 Hz, 2H), 7.35 (d, J =
8.70 Hz, 2H), 5.95 (d, J = 9.30 Hz, 1H), 5.55 (d, J = 9.90 Hz, 1H),
1.43 (s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 153.7, 135.6,
132.1, 130.4 (2), 128.6 (2), 93.8, 81.3, 63.9, 28.0 (3) ppm. MS
(ESMS/[M + Na]+): calcd for C13H15Br2ClN2O4Na 480.8958, found
480.8944. IR (KBr): ν = 3278, 2978, 1687, 1577, 1514, 1369, 1323,
1250, 1163, 831 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(4-methoxyphenyl)-2-
nitroethane (3c). White solid (427 mg, 94%). Mp = 129−131 °C. 1H
NMR (300 MHz, CDCl3): δ 7.34 (d, J = 9.00 Hz, 2H), 6.89 (d, J =
9.00 Hz, 2H), 5.91 (d, J = 10.20 Hz, 1H), 5.54 (d, J = 9.60 Hz, 1H),
3.81 (s, 3H), 1.44 (s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ
160.2, 153.9, 130.2 (2), 125.4, 113.7 (2), 95.0, 81.0, 64.0, 55.1, 28.0
(3) ppm. MS (ESMS/[M + Na]+): calcd for C14H18Br2N2O5Na
476.9455, found 476.9453. IR (KBr): ν = 3313, 2976, 1689, 1576,
1508, 1302, 1244, 1169, 1034, 837 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(2-(benzyloxy)phenyl)-
2-nitroethane (13j). White solids (504 mg, 95%). Mp = 120−122 °C.
1H NMR (300 MHz, CDCl3): δ 7.50−7.32(m, 7H), 6.99 (d, J = 8.10
Hz, 2H), 6.39 (d, J = 9.60 Hz, 1H), 6.15 (d, J = 7.20 Hz, 1H), 5.15(s,
2H) 1.43 (s, 9H) ppm. 13C NMR (75.45 MHz, DMSO-d6): δ 155.6,
154.4, 136.8, 130.4, 129.8, 128.3 (2), 127.7 (2), 127.2, 123.8, 120.4,
112.4, 95.0, 79.4, 69.6, 56.7, 28.0 (3) ppm. MS (ESMS/[M + Na]+):
calcd for C20H22Br2N2O5Na 552.9769, found 552.9737. IR (KBr): ν =
3246, 3141, 2978, 1699, 1574, 1493, 1367, 1252, 1161, 1020, 748
cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(2,6-dichlorophenyl)-
2-nitroethane (3k). White solids (454 mg, 92%). Mp = 104−106 °C.
1H NMR (300 MHz, CDCl3): δ 7.45(d, J = 7.80 Hz, 1H), 7.35−7.24
(m, 2H), 7.12 (d, J = 10.50 Hz, 1H), 6.43 (d, J = 9.30 Hz, 1H), 1.45 (s,
9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 153.8, 138.6, 134.4,
130.7, 130.6, 130.0, 129.1, 91.6, 81.4, 62.3, 28.0 (3) ppm. MS (ESMS/
[M + Na]+): calcd for C13H14Br2Cl2N2O4Na 514.8567, found
514.8554. IR (KBr): ν = 3323, 2976, 1703, 1577, 1439, 1348, 1254,
1155, 1014, 769 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(3,4-dichlorophenyl)-
2-nitroethane (3l). White solids (434 mg, 88%). Mp = 156−158 °C.
1H NMR (300 MHz, CDCl3): δ 7.57 (s, 1H), 7.46 (d, J = 8.40 Hz,
1H), 7.29 (d, J = 8.40 Hz, 1H), 5.94 (d, J = 9.60 Hz, 1H), 5.55 (br,
1H), 1.44 (s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 153.7,
134.0, 133.9, 132.7, 131.0, 130.4, 128.5, 93.0, 81.7, 63.5, 28.1 (3) ppm.
MS (ESMS/[M + Na]+): calcd for C13H14Br2Cl2N2O4Na 514.8567,
found 514.8557. IR (KBr): ν = 3353, 3151, 2976, 1705, 1572, 1473,
1369, 1254, 1159, 1022, 777 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(4-fluorophenyl)-2-ni-
troethane (3m). White solids (438 mg, 99%). Mp = 118−120 °C. 1H
NMR (300 MHz, CDCl3): δ 7.42 (dd, J1 = 8.70 Hz, J2 = 5.10 Hz, 2H),
7.07 (t, J = 8.70 Hz, 2H), 5.96 (d, J = 9.00 Hz, 1H), 5.55 (br, 1H),
1.44 (s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 163.1 (d, J = 249
Hz), 153.8, 130.9 (d, J = 7.50 Hz), 129.5, 115.4 (d, J = 21.50 Hz),
94.2, 81.3, 63.8, 28.0 (3) ppm. MS (ESMS/[M + Na]+): calcd for
C13H15Br2FN2O4Na 464.9255, found 464.9247. IR (KBr): ν = 3398,
2985, 1697, 1577, 1506, 1369, 1321, 1232, 1167, 850 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(2-chlorophenyl)-2-ni-
1
troethane (3d). White solid (454 mg, 99%). Mp = 164−166 °C. H
NMR (300 MHz, CDCl3): δ 7.60 (br, 1H), 7.49−7.45 (m, 1H), 7.38−
7.34 (m, 2H), 6.70 (d, J = 10.20 Hz, 1H), 5.56 (br, 1H), 1.42 (s, 9H)
ppm. 13C NMR (75.45 MHz, CDCl3): δ 153.4, 135.6, 133.1, 130.6,
130.1, 128.4, 127.1, 93.1, 81.6, 59.8, 28.1 (3) ppm. MS (ESMS/[M +
Na]+): calcd for C13H15Br2ClN2O4Na 480.8958, found 480.8941. IR
(KBr): ν = 3357, 2987, 1709, 1577, 1473, 1365, 1155, 1045, 843 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-p-tolyl-2-nitroethane
1
(3e). White solid (416 mg, 95%). Mp = 108−110 °C. H NMR (300
MHz, CDCl3): δ 7.31 (d, J = 8.10 Hz, 2H), 7.18 (d, J = 8.10 Hz, 2H),
5.93 (d, J = 9.30 Hz, 1H), 5.56 (d, J = 9.00 Hz, 1H), 2.35 (s, 3H), 1.44
(s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 153.8, 139.4, 130.5,
129.0 (2), 128.8 (2), 94.8, 81.0, 64.3, 28.0, 21.0 (3) ppm. MS (ESMS/
[M + Na]+): calcd for C14H18Br2N2O4Na 460.9506, found 460.9479.
IR (KBr): ν = 3292, 2978, 1687, 1577, 1509, 1323, 1250, 1161, 1022,
845 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(4-(trifluoromethyl)-
phenyl)-2-nitroethane (3f). White solid (448 mg, 91%). Mp = 113−
1
115 °C. H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.70 Hz, 2H),
7.59 (d, J = 8.10 Hz, 2H), 6.04 (d, J = 10.20 Hz, 1H), 5.60 (d, J =
10.50 Hz, 1H), 1.43 (s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3) δ
153.8, 137.7, 131.6 (q, J = 32.82 Hz), 129.6 (2), 125.4, 125.3, 121.8,
93.2, 81.6, 64.1, 28.0 (3) ppm. MS (ESMS/[M + Na]+): calcd for
C14H15Br2F3N2O4Na 514.9223, found 514.9231. IR (KBr): ν = 3319,
2981, 1687, 1579, 1510, 1327, 1250, 1132, 1070, 839 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(4-bromophenyl)-2-ni-
1
troethane (3n). White solids (483 mg, 96%). Mp = 129−131 °C. H
NMR (300 MHz, CDCl3): δ 7.52 (d, J = 8.40 Hz, 2H), 7.32 (d, J =
8.40 Hz, 2H), 5.93 (d, J = 10.20 Hz, 1H), 5.54 (d, J = 10.20 Hz, 1H),
1.43 (s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 153.7, 132.7,
131.5 (2), 130.6 (2), 123.8, 93.7, 81.4, 63.9, 28.0 (3) ppm. MS
(ESMS/[M + Na]+): calcd for C13H15Br3N2O4Na 524.8454, found
524.8455. IR (KBr): ν = 3280, 2978, 1687, 1577, 1512, 1369, 1321,
1250, 1163, 837 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(4-cyanophenyl)-2-ni-
1
troethane (3g). White solids (435 mg, 97%). Mp = 146−148 °C. H
NMR (300 MHz, CDCl3): δ 7.69 (d, J = 8.40 Hz, 2H), 7.59 (d, J =
8.40 Hz, 2H), 6.03 (d, J = 10.20 Hz, 1H), 5.58 (d, J = 9.60 Hz, 1H),
1.43 (s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 153.6, 138.7,
131.9 (2), 129.9 (2), 117.8, 113.2, 92.6, 81.4, 63.9, 27.8 (3) ppm. MS
(ESMS/[M + Na]+): calcd for C14H15Br2N3O4Na 471.9302, found
471.9315. IR (KBr): ν = 3315, 2979, 2239, 1730, 1576, 1502, 1327,
1244, 1159, 833 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(3-fluorophenyl)-2-ni-
1
troethane (3o). White solids (433 mg, 98%). Mp = 135−137 °C. H
NMR (300 MHz, CDCl3): δ 7.36 (dd, J1 = 7.80 Hz, J2 = 13.80 Hz,
1H), 7.22 (d, J = 8.40 Hz, 1H), 7.13 (d, J = 9.60 Hz, 1H), 7.11 (t, J =
8.10 Hz, 1H), 5.97 (d, J = 9.00 Hz, 1H), 5.56 (d, J = 9.90 Hz, 1H),
1.44 (s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 162.2 (d, J = 247
Hz), 153.8, 136.0, 129.9 (d, J = 7.50 Hz), 125.0 (d, J = 3.20 Hz), 116.4
(d, J = 28.20 Hz), 116.1 (d, J = 30.20 Hz), 93.6, 81.4, 63.9, 28.0 (3)
ppm. MS (ESMS/[M + Na]+): calcd for C13H15Br2FN2O4Na
464.9255, found 464.9253. IR (KBr): ν = 3253, 3141, 2985, 1695,
1576, 1452, 1379, 1232, 1161, 1018, 775 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(naphthalen-2-yl)-2-
nitroethane (3h). White solids (431 mg, 91%). Mp = 139−141 °C. 1H
NMR (300 MHz, CDCl3): δ 7.91−7.84 (m, 4H), 7.55−7.52 (m, 3H),
6.16 (d, J = 9.60 Hz, 1H), 5.72 (d, J = 10.20 Hz, 1H), 1.44 (s, 9H)
ppm. 13C NMR (75.45 MHz, CDCl3): δ 153.9, 133.3, 132.5, 130.8,
129.3, 128.2, 128.1, 127.5, 127.0, 126.6, 125.5, 94.4, 81.2, 64.6, 28.0
(3) ppm. MS (ESMS/[M + Na]+): calcd for C17H18Br2N2O4Na:
496.9506; found 496.9549. IR (KBr): ν = 3261, 3149, 2983, 1709,
1574, 1506, 1363, 1254, 1159, 1018 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(3-bromophenyl)-2-ni-
1
troethane (3p). White solids (433 mg, 86%). Mp = 155−157 °C. H
NMR (300 MHz, CDCl3): δ 7.61 (s, 1H), 7.54 (d, J = 8.10 Hz, 1H),
7.37 (d, J = 7.80 Hz, 1H), 7.25 (t, J = 7.80 Hz, 1H), 5.94 (d, J = 10.20
Hz, 1H), 5.56 (d, J = 10.20 Hz, 1H), 1.44 (s, 9H) ppm. 13C NMR
(75.45 MHz, DMSO-d6): δ 154.5, 136.8, 132.1(2), 130.0, 129.0, 121.4,
93.8, 79.7, 64.0, 27.9 (3) ppm. MS (ESMS/[M + Na]+): calcd for
C13H15Br3N2O4Na 524.8454, found 524.8464. IR (KBr): ν = 3244,
3143, 2985, 1698, 1576, 1477, 1369, 1255, 1155, 1018, 847 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(3-bromo-4-methoxy-
phenyl)-2-nitroethane (3q). White solids (469 mg, 88%). Mp = 157−
1-(tert-Butoxyformamido)-2,2-dibromo-1-(naphthalen-1-yl)-2-
nitroethane (3i). White solids (389 mg, 82%). Mp = 201−203 °C. 1H
NMR (300 MHz, CDCl3) δ 8.42 (d, J = 7.50 Hz, 1H), 7.91 (t, J = 8.40
Hz, 2H), 7.78 (d, J = 6.60 Hz, 1H), 7.65 (t, J = 7.20 Hz, 1H), 7.56 (d, J
= 8.10 Hz, 1H), 7.51 (d, J = 8.10 Hz, 1H), 7.00 (d, J = 9.00 Hz, 1H),
5.71 (d, J = 8.40 Hz, 1H), 1.40 (s, 9H) ppm. 13C NMR (75.45 MHz,
DMSO-d6) δ 154.8, 133.1, 131.5, 131.4, 129.8, 128.9, 127.3, 126.9,
125.9, 125.0, 123.0, 94.4, 79.7, 57.8, 27.9 (3) ppm. MS (ESMS/[M +
Na]+): calcd for C17H18Br2N2O4Na 496.9506, found 496.9505. IR
1174
dx.doi.org/10.1021/jo302727v | J. Org. Chem. 2013, 78, 1171−1175

The Journal of Organic Chemistry
Article
1
159 °C. H NMR (300 MHz, CDCl3): δ 7.63 (d, J = 2.10 Hz, 1H),
(b) Thomas, G. Medicinal Chemistry: An Introduction; John Wiley &
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7.33 (dd, J1 = 8.80 Hz, J2 = 2.10 Hz, 1H), 6.87 (d, J = 8.80 Hz, 1H),
5.88 (d, J = 9.90 Hz, 1H), 5.50 (d, J = 9.90 Hz, 1H), 3.90 (s, 3H), 1.44
(s, 9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 155.9, 154.5, 133.7,
130.7, 127.7, 111.7, 110.3, 94.5, 79.6, 63.6, 56.2, 27.9 (3) ppm. MS
(ESMS/[M + Na]+): calcd for C14H17Br3N2O5Na 554.8560, found
554.8564. IR (KBr): ν = 3269, 3153, 2983, 1695, 1576, 1506, 1369,
1271, 1161, 1022, 845 cm−1.
1-(tert-Butoxyformamido)-2,2-dibromo-1-(2-methoxyphenyl)-2-
nitroethane (3r). White solids (445 mg, 98%). Mp = 153−155 °C. 1H
NMR (300 MHz, CDCl3): δ 7.37 (t, J = 6.90 Hz, 2H), 7.00−6.91 (m,
2H), 6.29 (d, J = 10.20 Hz, 1H), 6.05 (s, 1H), 3.85 (s, 3H), 1.44 (s,
9H) ppm. 13C NMR (75.45 MHz, CDCl3): δ 157.4, 154.1, 133.3,
130.7, 130.3, 120.5, 111.3, 80.8, 94.6, 61.2, 55.3, 28.1 (3) ppm. MS
(ESMS/[M + Na]+): calcd for C14H18Br2N2O5Na 476.9455, found
476.9447. IR (KBr): ν = 3251, 3138, 2976, 1693, 1576, 1493, 1361,
1248, 1159, 1022, 754 cm−1.
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1-(tert-Butoxyformamido)-2,2-dibromo-1-(3,4-dimethoxyphen-
yl)-2-nitroethane (3s). White solids (474 mg, 98%). Mp = 139−141
1
°C. H NMR (300 MHz, CDCl3): δ 6.98 (dd, J1 = 8.10 Hz, J2 = 2.10
Hz, 1H), 6.89 (d, J = 2.10 Hz, 1H), 6.84 (d, J = 8.10 Hz, 1H), 5.89 (d,
J = 9.90 Hz, 1H), 5.54 (d, J = 10.20 Hz, 1H), 3.89 (s, 3H), 3.88 (s,
3H), 1.44 (s, 9H) ppm. 13C NMR (75.45 MHz, DMSO-d6): δ 154.7,
149.4, 148.2, 126.1, 122.6, 113.2, 110.8, 95.4, 79.5, 64.5, 55.7, 55.4,
28.0 (3) ppm. MS (ESMS/[M + Na]+): calcd for C15H20Br2N2O6Na
506.9561, found 506.9587. IR (KBr): ν = 3359, 2972, 1693, 1574,
1502, 1352, 1315, 1246, 1155, 1024, 845 cm−1.
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1-(tert-Butoxyformamido)-2,2-dibromo-1-(4-tert-butylphenyl)-2-
nitroethane (3t). White solids (398 mg, 83%). Mp = 123−125 °C. 1H
NMR (300 MHz, CDCl3) δ 7.39−7.32 (m, 4H), 5.95 (d, J = 8.70 Hz,
1H), 5.58 (d, J = 8.70 Hz, 1H), 1.44 (s, 9H), 1.31 (s, 9H) ppm. 13C
NMR (75.45 MHz, CDCl3) δ 153.9, 152.5, 130.5, 128.7 (2), 125.4
(2), 94.7, 81.1, 64.2, 34.6, 31.1 (3), 28.1 (3) ppm. MS (ESMS/[M +
Na]+): calcd for C17H24Br2N2O6Na 502.9976, found 502.9997. IR
(KBr): ν = 3253, 3145, 2962, 1705, 1577, 1477, 1365, 1257, 1159,
1016, 837, 775 cm−1.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all pure products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: (Y.P.) 86-25-83593153, (G.L.) 001-806-742-1289. E-
mail: (Y.P.) yipan@nju.edu.cn, (G.L.) guigen.li@ttu.edu.
Notes
The authors declare no competing financial interest.
(14) Kotti, S.; Timmons, C.; Li, G. Chem. Biol. Drug. Des. 2006, 67,
101−114.
(15) Kattamuri, P. V.; Ai, T.; Pindi, S.; Sun, Y. W.; Gu, P.; Shi, M.; Li,
G. J. Org. Chem. 2011, 76, 2792−2797.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the NIH
(R21DA031860-01, G.L.), the National Natural Science
Foundation of China (No. 21102071, Y.P.), the Robert A.
Welch Foundation (D-1361, G.P.), the Fundamental Research
Funds for the Key Universities (Nos. 1107020522 and
1082020502, Y.P.), and the Jiangsu 333 program (Y.P.).
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1577. (b) Kaur, P.; Pindi, S.; Wever, W.; Rajale, T.; Li, G. J. Org. Chem.
2010, 75, 5144−5150.
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2011, 77, 20−29.
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Sinica 2011, 69, 2851−2858. (b) For both reported anhydrous
Na3PO4- and K3PO4-catalyzed aminohalogenation systems, 20−50
mol% of catalyst was required.
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