Regiospecific synthesis of novel cyclic nitrostyrenes and 3-substituted 2-nitronaphthalenes

Article abstract of DOI:10.1055/s-0033-1338867

A two-step, practical, regiospecific, and readily scalable benzannulation protocol for the preparation of novel 3-alkyl- and 3-aryl-substituted 2-nitronaphthalenes is disclosed. Addition of a β-nitrostyrene or nitroalkene to a solution of freshly prepared lithiated o-tolualdehyde tert-butyl imine first leads to the formation of a nitronate, via rapid 1,4-addition, then an intramolecular aza-Henry reaction takes place to afford a six-membered carbocycle. Subsequent treatment of the reaction mixture with aqueous acid affords novel substituted cyclic nitrostyrenes that can be conveniently aromatized via a one-pot radical-induced bromination and elimination sequence to furnish the corresponding 3-alkyl- or 3-aryl-2-nitronaphthalenes in excellent yields. The straightforward syntheses of 2-aminonaphthalenes, substituted BINAMs, 2-naphthols as well as tricyclic fused 1,2,3-triazoles are also described. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338867

FEATURE ARTICLE
▌1719
feature article
Regiospecific Synthesis of Novel Cyclic Nitrostyrenes and 3-Substituted
2-Nitronaphthalenes
Regiospecific Synthesis of 3-Substituted 2-Nitronaphthalenes
Craig Keene, László Kürti*
Division of Chemistry, Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas TX 75390, USA
Fax +1(214)6488856; E-mail: laszlo.kurti@utsouthwestern.edu
Received: 02.04.2013; Accepted after revision: 07.05.2013
R1
R2
R1
R2
Abstract: A two-step, practical, regiospecific, and readily scalable
benzannulation protocol for the preparation of novel 3-alkyl- and 3-
aryl-substituted 2-nitronaphthalenes is disclosed. Addition of a β-
nitrostyrene or nitroalkene to a solution of freshly prepared lithiated
o-tolualdehyde tert-butyl imine first leads to the formation of a ni-
tronate, via rapid 1,4-addition, then an intramolecular aza-Henry re-
action takes place to afford a six-membered carbocycle. Subsequent
treatment of the reaction mixture with aqueous acid affords novel
substituted cyclic nitrostyrenes that can be conveniently aromatized
via a one-pot radical-induced bromination and elimination sequence
to furnish the corresponding 3-alkyl- or 3-aryl-2-nitronaphthalenes
in excellent yields. The straightforward syntheses of 2-aminonaph-
thalenes, substituted BINAMs, 2-naphthols as well as tricyclic
fused 1,2,3-triazoles are also described.
R1
NH2
3 steps
chiral
acid catalyst
NH2
NH2
R2
NH
NH
R2
(S)
R2
atroposelective
[3,3]-
rearrangement
R1
R1
substituted
2-naphthylamines
up to
90% yield, 86% ee
binaphthyl hydrazines
Scheme 1 The first scalable organocatalytic atroposelective synthe-
sis of BINAM derivatives
Traditional routes to substituted 2-naphthylamines begin
from a limited selection of 2-acetonaphthones or 2-te-
tralones and require three or more steps to prepare the tar-
get molecules (Scheme 2); the overall yields are generally
low to moderate to (25–50%).1,3 A more recent route to
substituted 2-naphthylamines involves the transition-
metal-catalyzed cross-coupling of internal alkynes with
(2-iodophenyl)acetonitrile; while the isolated yield and
the regioselectivity are both good, the structural diversity
of the products is narrow, which limits the usefulness of
this approach.4
Key words: cyclic nitrostyrene, 2-nitronaphthalene, 2-aminonaph-
thalene, BINAM, fused triazole
Our group is pursuing the development of powerful and
practical new methods for the synthesis of highly func-
tionalized symmetrical and unsymmetrical biaryls. Given
the remarkable track record of axially chiral biaryls as
highly efficient ligands in asymmetric synthesis, it is clear
that convenient synthetic access to many structurally di-
verse and uniquely functionalized biaryls will have a pro-
found impact on the discovery of new chemical reactivity.
O
R1
R1
3
R1
3
NH2
O
steps
steps
R2
R2
R2
substituted
2-tetralones
The first scalable organocatalytic atroposelective synthe-
sis of BINAM derivatives was recently demonstrated in
our laboratory utilizing a remarkably efficient [3,3]-sig-
matropic rearrangement of binaphthyl hydrazines in the
presence of 5–20 mol% chiral acid catalysts (Scheme 1).1
The required binaphthyl hydrazine substrates were pre-
pared from the corresponding substituted 2-naphthyl-
amines via a three-step procedure2 that involved: (a)
diazotization, (b) reduction of the diazonium salt to the
corresponding symmetrical azo compound, and (c) reduc-
tion of the azo group with Zn/NH4Cl. However, a conve-
nient and readily scalable synthetic access to a wide
variety of substituted 2-naphthylamines, especially to 3-
alkyl- and 3-aryl-2-naphthylamines, remains a significant
challenge.
substituted
2-naphthylamines
substituted
2-acetonaphthones
regio-
regio-
selectivity
issues
>1
step
1
step
selectivity
1
step
issues
R2
R1
O
CN
R1
+
+
X
I
R2
R
(limited substrate scope)
(limited substrate scope)
(limited substrate scope)
Scheme 2 Traditional and more recent routes for the preparation of
substituted 2-naphthylamines
After we have prepared several 2-naphthylamine sub-
strates using both the traditional and newer routes, it be-
came clear that a new synthetic approach had to be
developed that addresses the shortcomings of existing
methods. In particular we had difficulties with the prepa-
ration of multi-gram quantities of substituted 2-naphthyl-
amines since several steps failed to work efficiently on
larger scale (>10 mmol). Therefore, we decided to devel-
op a convergent route to achieve the rapid and practical
synthesis of a variety of 3-substituted 2-naphthylamines.
SYNTHESIS 2013, 45, 1719–1729
Advanced online publication: 07.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338867; Art ID: SS-2013-C0260-FA
© Georg Thieme Verlag Stuttgart · New York

1720
C. Keene, L. Kürti
FEATURE ARTICLE
Three de novo synthetic approaches to substituted naph- trostyrenes and nitroalkenes were selected as coupling
thalenes I–III that rely on tandem 1,4-addition/intramo- partners for three important reasons: (a) they may be read-
lecular cyclization steps are highlighted in Scheme 3.5 ily prepared from inexpensive precursors in decagram to
These methods deliver useful functionalized naphthalene kilogram quantities; (b) the nitro group will occupy the 2-
derivatives, however, the aromatic starting materials are position in the new bicyclic system and thus it perfectly
highly specialized, the reaction conditions are often harsh, maps on the structure of 2-aminonaphthalenes; and (c) the
and the isolated yields range from moderate to low. Not- nitro group is often referred to as a chemical chameleon
withstanding the above mentioned drawbacks, we were due to its extraordinary versatility as a functional group,
inspired by these tandem approaches when our two-step therefore, it will allow the introduction of many other use-
regiospecific benzannulation protocol was designed ful functionalities on the naphthalene nucleus.8
(Scheme 3).
Benzylic lithium species 1a was prepared from o-tolual-
We decided to use the readily available lithiated o-tolu- dehyde tert-butyl imine (1) based on conditions described
aldehyde tert-butyl imine6 1a as our starting material. earlier:6 stoichiometric n-butyllithium is added over 30–
This benzylic lithium species has been shown recently by 40 minutes to a solution of 1 and catalytic amounts (15
Myers to be an excellent nucleophile that easily adds mol%) of 2,2,6,6-tetramethylpiperidine (TMP) in THF at
across the carbon–nitrogen triple bond in aromatic nitriles 0 °C (Table 1). The resulting lateral-lithiated species 1a
to afford substituted isoquinolines.7 Our hypothesis was forms a deep-purple solution, which is then aged for 45
that β-nitrostyrenes/nitroalkenes 2 should also readily re- minutes before cooling to –78 °C. Next, the solution of a
act with 1a and, upon acidic workup, should yield novel particular nitroalkene 2a–l in THF is added over 10 min-
cyclic nitrostyrenes 3, even though these electrophiles utes and the reaction mixture is stirred for an additional 30
have not been previously reported to undergo this cycliza- to 60 minutes. Water is then added into the mixture fol-
tion. Likewise, it appeared reasonable that upon oxida- lowed by excess (4 equiv) of concentrated aqueous HCl
tion, cyclic nitrostyrenes
3
would furnish the solution.
corresponding 3-substituted 2-nitronaphthalenes 4. β-Ni-
Biographical Sketches█
László Kürti was born and postdoctoral
raised in Hungary and re- (2006–2010) as a Damon sembly of heterocyclic com-
ceived his Diploma from the Runyon Cancer Fellow in pounds to aid drug
training processes for the rapid as-
University of Debrecen, the group of Professor E. J. discovery. He is the co-
Hungary where he conduct- Corey at Harvard Universi- author of three widely used
ed research in the laboratory ty, he began his independent textbooks/reference books.
of Professor Sándor Antus. career at UT Southwestern In 2005 he published with
Subsequently, he received Medical Center in Dallas in Barbara Czakó the textbook
his MS degree at the Uni- September 2010. László’s Strategic Applications of
versity of Missouri-Colum- current research interests in- Named Reactions in Organ-
bia working with Professor clude the development of ic Synthesis, in 2007 with
Michael Harmata, and his new strategies for the atro- Professor Corey the text-
Ph.D. degree (2006) in syn- poselective synthesis of book Molecules and Medi-
thetic organic chemistry un- structurally divserse biaryls cine, and in 2010 the
der the supervision of that will serve as novel li- textbook/reference
book
Professor Amos B. Smith III gands and catalysts as well Enantioselective Chemical
(University of Pennsylva- as transition-metal-free C– Synthesis: Methods, Logic
nia). After completing his C and C–N bond-forming and Practice.
Craig Keene was born in joined the graduate program ment of new synthetic
1988 in Dallas, Texas. He at UT Southwestern Medi- methods for the construc-
began his studies in Biology cal Center and since 2012, tion of novel functionalized
at Texas Tech University has been a Ph.D. student in biaryls, heterocycles, and
(Lubbock, Texas) in 2006 the Kürti Laboratory. His biomolecules.
and obtained his Bachelor’s research interests are cen-
degree in 2010. In 2011 he tered around the develop-
Synthesis 2013, 45, 1719–1729
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Regiospecific Synthesis of 3-Substituted 2-Nitronaphthalenes
1721
previous work:
van Leusen, A.M (1978):
O
O
EWG
EWG
R
2 steps
H
R
OEt
(I)
NaH (2–3 equiv)
1,2-DME, reflux
31–80%
Ts
Makosza, M. (1994):
R1
R1
EWG
EWG
EWG
K2CO3, 18-crown-6
SO2Ph
R2
(II)
+
MeCN, 80 °C, 3–5 h
40–95%
O2N
EWG
O2N
R2
O
Mal, D. (2011):
R2
R2
R3
R4
LDA or LHMDS
R3
R4
THF, –78 °C to r.t.
R1
O
R1
(III)
+
20–67%
CO2Me
O
OH
this work:
NO2
N-t-Bu
R
NO2
NO2
2
oxidation
THF, –78 °C
then HCl (aq)
Li
R
R
1a
3
4
Scheme 3 Representative de novo synthetic approaches I–III to substituted naphthalenes, including our two-step, regiospecific, and scalable
benzannulation protocol
Table 1 Synthesis of Novel Cyclic Nitrostyrenes
NO2
2a–l
R
TMP
(15 mol%)
n-BuLi
(1 equiv)
THF, –78 °C
30–60 min
Nt-Bu
H
Nt-Bu
NO2
R
(1.1 equiv)
H
Li
then quench
with HCl (aq)
THF, 0 °C
40 min
Me
1–60 mmol scale
1
1a
3a–l
Entry
Nitroalkene
Product
Yield (%)a
76
NO2
NO2
NO2
NO2
1b
2a
3a
3b
2c
2b
42
NO2
NO2
3c
2c
3c
67
84
MeO
OMe
NO2
MeO
MeO
NO2
OMe
OMe
4d
2d
3d
OMe
OMe
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1719–1729

1722
C. Keene, L. Kürti
FEATURE ARTICLE
Table 1 Synthesis of Novel Cyclic Nitrostyrenes (continued)
NO2
2a–l
R
TMP
(15 mol%)
n-BuLi
(1 equiv)
THF, –78 °C
30–60 min
Nt-Bu
H
Nt-Bu
NO2
R
(1.1 equiv)
H
Li
then quench
with HCl (aq)
THF, 0 °C
40 min
Me
1–60 mmol scale
1
1a
3a–l
Entry
Nitroalkene
Product
Yield (%)a
82
NO2
NO2
O
O
5c
2e
3e
3f
O
O
NO2
NO2
6c
2f
62
52
56
F
F
NO2
NO2
7e
2g
2h
3g
3h
CF3
F3C
NO2
NO2
8c,f
NO2
O2N
NO2
NO2
NO2
9c
2i
2j
3i
3j
54
53
NO2
10c
NO2
F
F
F
F
F
NO2
F
11e,g
2k
2l
3k
3l
57
F
F
F
CHO
NO2
NO2
12e,g
42
O2N
O2N
a Isolated yield.
b Reaction carried out on a 60 mmol scale.
c Reaction carried out on a 20–25 mmol scale.
d Reaction carried out on a 30 mmol scale.
e Reaction carried out on a 9–10 mmol scale.
f Substrate 1a was transmetalated with CuBr before the addition of 2h.
g Two equivalents of 1 were used.
The acidified reaction mixture is then warmed to room coupling partners (Table 1, entries 4 and 5), while elec-
temperature and subsequently neutralized with aqueous tron-poor β-nitrostyrenes 2f–h furnished the cyclized
sodium carbonate solution. Following extraction and products in somewhat lower yields (entries 6–8). It is
chromatographic purification, cyclic nitrostyrenes 3a–l noteworthy that o-nitro-substituted β-nitrostyrene 2h did
are isolated as yellow crystalline solids (Table 1).
not undergo the parent transformation, the reaction in-
stead led to a complex mixture of inseparable products.
Presumably, the presence of two nitro groups leads to
The highest yields of cyclic nitrostyrenes 3 were achieved
when employing electron-rich β-nitrostyrenes 2c–e as
Synthesis 2013, 45, 1719–1729
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Regiospecific Synthesis of 3-Substituted 2-Nitronaphthalenes
1723
many side-reactions that usually take place via complex tion of compounds 3a–l would lead to derivatives in
electron-transfer processes. However, by transmetalating which HBr elimination would be facile. We were delight-
1a with 1 equivalent of CuBr, the 1,4-addition step pro- ed to find that bromination of cyclic nitrostyrenes 3a–l un-
ceeded more cleanly; apparently fewer side reactions took der radical conditions using catalytic amounts (15 mol%)
place. We were pleased to observe that nitroalkenes 2i and of dibenzoyl peroxide and excess N-bromosuccinamide
2j worked well as substrates demonstrating that besides (1.7 equiv) at elevated temperatures (>80 °C) in DCE fur-
substituted aromatic rings, alkyl substituents may also be nished the corresponding 3-substituted 2-nitronaphtha-
introduced. When pentafluoronitrostyrene 2k (entry 11) lenes 4a–l in excellent isolated yields (Table 2). It should
was used as the coupling partner, in addition to the expect- be noted that compounds 3e and 3l did not undergo aro-
ed 1,4-addition/cyclization, a nucleophilic aromatic sub- matization under these conditions; complex mixtures of
stitution reaction (SNAr) also took place to furnish 3k. We products were obtained instead.
presume that the SNAr reaction is faster than the tandem
1,4-addition/intramolecular aza-Henry reaction of 1a with
2k. Indeed, we were unable to isolate even trace amounts
Table 2 Aromatization of Cyclic Nitrostyrenes to the Corresponding
3-Substituted 2-Nitronaphthalenes
NO2
R
NO2
R
of the expected C6F5-substituted cyclic nitrostyrene prod-
uct; this compound, however, does not undergo SNAr re-
action as it is no longer activated for this transformation.
NBS (1.7 equiv)
BzOOBz (15 mol%)
DCE, reflux
(1–20 mmol scale)
3a–l
4a–l
The formation of cyclic nitrostyrenes 3 from 1a and 2 is
rationalized by a mechanism proposed in Scheme 4. At
low temperature, benzylic lithium species 1a rapidly adds
to 2 in a 1,4-fashion to generate a nitronate intermediate
1b, which in turn undergoes an intramolecular aza-Henry
reaction to form a six-membered carbocycle 1c. When the
reaction mixture is treated with aqueous acid, the strongly
basic nitrogen atom in 1c is protonated and a facile elimi-
nation of tert-butylamine takes place to afford the cyclic
nitrostyrene 3.
Entrya,b
Substrate 3
Time (h)
Yield of 4 (%)
1c
2d
3
3a
3b
3c
3d
3e
3f
10
11
14
15
12
16
13
1
99
99
74
98
0
4
5
6e
7
96
95
95
96
85
32
0
Li
3g
3h
3i
O
N
t-Bu
t-Bu
O
N
intramolecular
aza-Henry
reaction
N
1,4-
addition
8e
9f
10f
11
12
N
Li
O
O
10
18
14
6
R
R
1a
2
1b
3j
Li
t-Bu
3k
3l
t-Bu
H2N
O
N
N
NO2
loss of
t-BuNH2
NO2
HCl
O
H
R
H2O
R
a Reactions were performed on a 1 mmol scale unless indicated other-
wise.
R
3
1c
1d
b Reaction times exceeding 12 h lead to the formation of some de-
nitrated product.
Scheme 4 Proposed mechanism for the formation of 3 from 1a and
2 via a tandem 1,4-addition/intramolecular aza-Henry reaction pro-
cess
c Reaction carried out on a 20 mmol scale.
d Reaction carried out on a 6.5–7 mmol scale.
e Reaction carried out on a 3–4.5 mmol scale.
f Reaction carried out on a 9–10 mmol scale.
By securing multi-gram quantities of cyclic nitrostyrenes
3a–l (Table 1), the stage was set for their conversion into
the corresponding 3-substituted 2-nitronaphthalenes 4. The synthetic utility of the novel cyclic nitrostyrene 3 and
We were surprised to find that these compounds were re- 3-substituted 2-nitronaphthalene 4 products was explored
markably stable towards aromatization via oxidative next. For this purpose compounds 3a and 4a were selected
methods; traditional methods of aromatization (e.g., dehy-
drogenation involving Pd/C and DDQ) were largely un-
successful.9 Only minimal conversion into the
as representative substrates (Scheme 5, isolated yields are
shown). The 1,4-reduction10 of compound 3a with NaBH4
cleanly gave the corresponding cyclic nitroalkane 5, while
corresponding 2-nitronaphthalenes 4 was observed even reduction with LiAlH4 furnished an interesting cyclic am-
after 48 hours at reflux temperatures in high-boiling sol- phetamine analogue 6. Heating 3a with NaN3 in DMSO
vents (i.e., chlorobenzene, xylenes). We hypothesized that afforded a previously unknown fused 1,2,3-triazole 7 in
the introduction of a bromine atom at the benzylic posi- nearly quantitative yield.11
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1719–1729

1724
C. Keene, L. Kürti
FEATURE ARTICLE
low overall yields). The novel synthetic approach that is
presented in this manuscript addresses all of these issues
effectively. The homo-and heterocoupling of 3-substitut-
ed 2-aminonaphthalenes to the corresponding enantio-
merically enriched BINAM derivatives as well as the
efficient conversion of 3 and 4 into a number of structur-
ally diverse functionalized biaryls are currently underway
in our laboratory.
NaBH4
(3.5 equiv)
THF–EtOH
(2:1)
N
N
NaN3
NO2
Ph
NO2
Ph
NH
(1 equiv)
DMSO
heat, 3 h
96%
50 °C, 5 h
52%
Ph
3a
5
7
NBS
(1.7 equiv)
BzOOBz
(15 mol%)
DCE
reflux,10 h
99%
LiAlH4 (2 equiv)
THF, reflux, 3 h
NH2
64%
Ph
6
All reactions were carried out in oven-dried glassware under an at-
mosphere of argon with magnetic stirring. All reagents, including
the aromatic aldehydes, TMP, and nitromethane were purchased
from Sigma-Aldrich Co. and used without further purification. Sol-
vents were dried by passage through an activated alumina column
under argon. Liquids and solutions were transferred via syringe. All
reactions were monitored by TLC with E. Merck silica gel 60 F254
precoated plates (0.25 mm). Silica gel (particle size 0.032–0.063
mm) purchased from SiliCycle was used for flash chromatography.
Ph
NO2
Ph
OH
Ph
NH2
NH2
4a
10
Ph
H2, Pd/C
(15 mol%)
3,3'-di-Ph-BINAM
90%
EtOAc–CH2Cl2
(2:1)
r.t., 10 h
H2O
heat
11
48%
1H and 13C NMR spectra were recorded on a Bruker AV-400 spec-
trometer operating at 400 MHz for proton and 100 MHz for carbon
nuclei using CDCl3 as solvent, respectively. Chemical shifts are ex-
pressed as parts per million (δ, ppm) and are referenced to 7.26
(CDCl3) for 1H NMR and 77.00 (CDCl3) for 13C NMR. Standard ab-
breviations are used to denote signal multiplicities. High-resolution
mass spectrometry was performed on a Shimadzu LCMS-IT-TOF
under the conditions of electrospray ionization (ESI) in both posi-
tive and negative mode. IR spectra were recorded on a Shimadzu
IRPrestige-21 (FT-IR Spectrophotometer).
BF3-OEt2
(1.2 equiv)
t-BuONO
(1.5 equiv)
FeCl3 (4.5 equiv)
N2BF4
Ph
NH2
Ph
H2O
90 °C, 72 h
38%
CH2Cl2
0 °C to r.t., 1 h
90%
9
8
Scheme 5 Synthetic utility of cyclic nitrostyrenes and 3-substituted
2-nitronaphthalenes
o-Tolualdehyde tert-Butyl Imine (1)
The nitro group is stable towards a variety of oxidizing re-
agents and conditions, whereas the amino group tends to
undergo facile oxidation even when exposed to air. For
this reason, 2-nitronaphthalenes are excellent surrogates
to 2-aminonaphthalenes, which are known to undergo air
oxidation. A mild Pd/C-catalyzed hydrogenation of 4a in
a mixture of dichloromethane and ethyl acetate gave 3-
phenyl-2-naphthylamine (8) in high yield (Scheme 5); this
approach to 8 is significantly more effective than those re-
ported in the past.12 Preparation of 3-phenyl-2-naphthol13
(10) could also be achieved via a highly stable diazonium
tetrafluoroborate salt 9.14 Finally, we were excited to find
that treatment of 8 with iron(III) chloride afforded 3,3′-di-
phenyl-BINAM (11).15 This transformation proceeds very
cleanly; however, liberation of 11 from its various Fe(III)
complexes is nontrivial and has not yet been optimized. It
is anticipated that other 3-aryl- and 3-alkyl-substituted 2-
aminonaphthalenes will undergo similar oxidative dimer-
ization to afford 3,3′-disubstituted 2,2′-diaminonaphtha-
lenes.
A 500 mL round-bottom flask was charged with o-tolualdehyde
(5.96 mL, 50 mmol, 1 equiv), tert-butylamine (11.56 mL, 110
mmol, 2.2 equiv), and toluene (50 mL). The resulting solution was
heated at reflux for 6 h. The solution was then allowed to cool to r.t.
and the solvent was removed in vacuo. Purification was performed
by vacuum distillation (70–73 °C/0.6 mmHg), which afforded 1 as
a colorless oil; yield: 8.41 g (96%).
1H NMR (400 MHz, CDCl3): δ = 8.61 (s, 1 H), 7.89 (dd, J1 = 7.4 Hz,
J2 = 1.7 Hz, 1 H), 7.32–7.22 (m, 2 H), 7.20–7.16 (m, 1 H), 2.52 (s,
3 H), 1.35 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 153.7, 137.0, 135.1, 130.5, 129.6,
127.0, 126.1, 57.5, 29.7, 19.1.
NMR spectra are in agreement with the published values.16
β-Nitrostyrenes 2a–l; trans-β-Nitrostyrene (2a);
Typical Procedure
β-Nitrostyrenes 2a–l were prepared according to the typical proce-
dure detailed below for compound 2a.
A 500 mL round-bottom flask, equipped with a mechanical stirrer
and an internal thermocouple, was charged with benzaldehyde (50.5
mL, 500 mmol, 1 equiv), nitromethane (28.3 mL, 500 mmol, 1
equiv), and reagent grade MeOH (100 mL). The resulting solution
was then cooled to 0 °C in an ice bath. Next, a solution of NaOH (20
g, 500 mmol, 1 equiv) in H2O (20 mL) was then added dropwise at
a rate so that the internal temperature does not rise above 15 °C. Af-
ter the addition of the NaOH solution was complete, the resulting
thick white paste was stirred for an additional 15 min before ice wa-
ter (200 mL) was added; most of the white solid dissolved as a re-
sult. The reaction mixture was then transferred to a 500 mL
In summary, we have developed a two-step, practical, re-
giospecific, and readily scalable benzannulation method
for the preparation of 3-substituted 2-nitronaphthalenes 4
via novel cyclic nitrostyrenes 3. These products are syn-
thetically versatile as they can be converted into many
other valuable compounds such as substituted 2-amino-
naphthalenes, BINAMs, 2-naphthols, and fused 1,2,3-tri- separatory funnel and slowly added to a 2 L Erlenmeyer equipped
with a stir bar and containing a solution of aq HCl [prepared from
concd HCl (37%, 150 mL) and H2O (150 mL)]. After the transfer
was complete, stirring was continued for an additional 15–30 min
during which time a precipitate was formed. The precipitate was
then filtered, washed with H2O (75 mL), and air dried in vacuo. Re-
crystallization from EtOH afforded 46.2 g of trans-β-nitrostyrene
azoles. In the past, the preparation of substituted 2-
aminonaphthalenes was a significant synthetic challenge
as the various routes often required several steps, suffered
from regioselectivity issues, limited scope of substrates,
and poor material throughput (i.e., due to the generally
Synthesis 2013, 45, 1719–1729
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Regiospecific Synthesis of 3-Substituted 2-Nitronaphthalenes
1725
(2a) as yellow needles; yield: 46.2 g (62%); mp 55–58 °C (Lit.17 mp
55–58 °C).
1H NMR (400 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.42 (dd, J1 = 7.0 Hz,
J2 = 1.9 Hz, 1 H), 7.37–7.29 (m, 2 H), 7.13 (d, J1 = 8 Hz, 1 H), 7.04–
7.01 (m, 2 H), 6.74–6.71 (m, 2 H), 4.50 (dd, J1 = 8.7 Hz, J2 = 1.7
Hz, 1 H), 3.71 (s, 3 H), 3.65–3.58 (m, 1 H), 3.12 (dd, J1 = 16.4 Hz,
J2 = 1.7 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ = 158.76, 150.15, 134.77, 132.07,
131.89, 131.70, 130.05, 129.76, 128.61, 127.76, 127.40, 113.99,
55.06, 37.38, 37.1.
Cyclic Nitrostyrenes 3a–l; General Procedure
o-Tolualdehyde imine 1 (3.51 g, 20 mmol, 1 equiv) was mixed with
of 2,2,6,6-tetramethylpiperidine (0.5 mL, 15 mol%) and anhyd THF
(20 mL). The solution was then transferred to a flame-dried 100 mL
round-bottom flask equipped with a magnetic stir bar and an inter-
nal thermocouple, and cooled to 0 °C in an ice bath. Next a solution
of 1.6 M n-BuLi in hexanes (13.13 mL, 21 mmol, 1.05 equiv) was
added dropwise via syringe pump so that the internal temperature
was never allowed to rise above 0 °C. When the addition was com-
plete, the resulting deep-purple solution was allowed to stir at 0 °C
for an additional 40 min and then cooled to –70 °C in a dry ice/ace-
tone bath. Next, a solution of a particular nitroalkene 2 (20 mmol, 1
equiv) in THF (20 mL) was added at –70 °C over 5 min. The reac-
tion mixture was stirred for an additional 30 to 60 min until the start-
ing materials had all been consumed (as shown by TLC analysis,
eluent: EtOAc–hexanes). H2O (10 mL, 0.5 mL/mmol of substrate)
was then injected rapidly into the flask (over 30 sec), followed by
concd HCl (37%, 6.5 mL) causing a rapid increase in temperature
to about –10 °C. The quenched reaction mixture was allowed to
warm to r.t. by placing the flask into a Dewar filled with H2O, and
an additional 30 min of stirring was performed at r.t. Excess HCl
was neutralized with a solution of sat. aq Na2CO3 (100 mL) and the
biphasic reaction mixture was extracted with CH2Cl2 (4 × 100 mL).
The combined organic layers were dried (MgSO4), filtered, and the
solvent was removed in vacuo. The crude product was purified via
column chromatography (EtOAc–hexanes).
HRMS (ESI): m/z calcd for C16H13NO2 + Na (M + Na+): 304.0944;
found: 304.0932.
3d
Reaction was carried out on a 30 mmol scale; yield: 8.6 g (84%);
yellow crystalline solid; mp 115.0–115.8 °C; Rf = 0.1 (10%
EtOAc–hexanes).
IR (ATR): 1530, 1472, 1441, 1408, 1348 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.05 (s, 1 H), 7.39 (dd, J1 = 7.3 Hz,
J2 = 1.5 Hz, 1 H), 7.33–7.24 (m, 2 H), 7.12 (d, J1 = 4 Hz, 1 H), 6.29
(s, 1 H), 4.44 (d, J1 = 8.5 Hz, 1 H), 3.73 (s, 3 H), 3.62 (s, 6 H), 3.62–
3.56 (m, 1 H), 3.12 (dd, J1 = 16.4 Hz, J2 = 1.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 152.97, 149.86, 136.97, 135.56,
134.82, 132.01, 131.71, 129.82, 129.55, 128.52, 127.38, 103.50,
60.51, 55.66, 38.22, 36.93.
3e
Reaction was carried out on a 20 mmol scale; yield: 4.84 g (82%);
red/yellow oil; Rf = 0.22 (10% EtOAc–hexanes).
IR (thin film): 1263, 731 cm–1.
3a
1H NMR (400 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.41 (dd, J1 = 7.1 Hz,
J2 = 1.9 Hz, 1 H), 7.37–7.27 (m, 2 H), 7.13 (d, J1 = 7.2 Hz, 1 H),
6.65–6.54 (m, 3 H), 5.85 (q, J1 = 1.4 Hz, 2 H), 4.47 (dd, J1 = 8.7 Hz,
J2 = 1.6 Hz, 1 H), 3.60 (ddt, J1 = 16.5 Hz, J2 = 8.7 Hz, J3 = 1.3 Hz,
1 H), 3.11 (dd, J1 = 16.4 Hz, J2 = 1.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 149.82, 147.66, 146.75, 134.61,
133.78, 132.14, 131.81, 130.15, 129.60, 128.60, 127.48, 119.90,
108.34, 107.18, 100.92, 37.86, 37.21.
Reaction was carried out on a 60 mmol scale; yield: 11.3 g (76%);
yellow crystalline needles; mp 132.6–134.6 °C; Rf = 0.2 (5%
EtOAc–hexanes).
IR (ATR): 1641, 1504, 1492, 1454, 1315 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.44 (dd, J1 = 7.1 Hz,
J2 = 1.8 Hz, 2 H), 7.36–7.31 (m, 2 H), 7.22–7.19 (m, 3 H), 7.14–
7.11 (m, 3 H), 4.56 (dd, J1 = 8.7 Hz, J2 = 1.7 Hz, 1 H), 3.65 (dd, J1 =
16.4 Hz, J2 = 8.7 Hz, 2 H), 3.16 (dd, J1 = 16.4 Hz, J2 = 1.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 149.77, 139.96, 134.65, 132.28,
131.75, 130.10, 129.72, 128.66, 128.58, 127.44, 127.31, 126.67,
38.20, 37.04.
HRMS (ESI): m/z calcd for C17H13NO4 + Na [M + Na]+: 318.0737;
found: 318.0733.
3f
HRMS (ESI): m/z calcd for C16H13NO2 (M + H)+: 252.1019; found:
252.1027.
Reaction was carried out on a 20 mmol scale; yield: 5.35 g (62%);
yellow crystalline solid; mp 118.4–119.4 °C; Rf = 0.25 (10%
EtOAc–hexanes).
IR (ATR): 1639, 1504, 1450, 1331, 1308, 1223, 1155 cm–1.
3b
Reaction was carried out on a 20 mmol scale; yield: 2.53 g (42%);
1H NMR (400 MHz, CDCl3): δ = 7.43 (dd, J1 = 7.2 Hz, J1 = 1.7 Hz,
1 H), 7.34 (ddd, J1 = 9.5 Hz, J2 = 7.0 Hz, J3 = 1.4 Hz, 2 H), 7.15–
7.11 (m, 1 H), 7.10–7.03 (m, 2 H), 6.91–6.83 (m, 2 H), 4.53 (dd,
J1 = 8.7 Hz, J2 = 1.7 Hz, 1 H), 3.67–3.57 (m, 1 H), 3.11 (dd,
J1 = 16.4 Hz, J2 = 1.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.99 (d, J1 = 245.7 Hz), 149.72,
135.76 (d, J4 = 3.3 Hz), 134.44, 132.31, 131.92, 130.20, 129.61,
128.64, 128.30 (d, J3 = 8.1 Hz), 127.59, 115.62 (d, J2 = 21.4 Hz),
37.51, 37.08.
yellow solid; mp 183.2–186.5 °C; Rf = 0.2 (5% EtOAc–hexanes).
IR (ATR): 1634, 1568, 1495, 1308, 1227 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.33 (s, 1 H), 8.29 (d, J1 = 8.55 Hz,
1 H), 7.90 (d, J1 = 12 Hz, 1 H), 7.71–7.64 (m, 2 H), 7.56 (ddd,
J1 = 8.0 Hz, J2 = 6.8 Hz, J3 = 1.1 Hz, 1 H), 7.48 (dd, J1 = 7.20 Hz,
J2 = 1.70 Hz, 1 H), 7.30–7.24 (m, 2 H), 7.18 (dd, J1 = 8.20 Hz,
J2 = 7.20 Hz, 1 H), 7.01 (dd, J1 = 7.20 Hz, J2 = 1.20 Hz, 1 H), 6.94
(d, J1 = 8 Hz, 1 H), 5.45 (d, J1 = 9.0 Hz, 1 H), 3.73 (dd, J1 = 8 Hz,
J2 = 8 Hz, 1 H), 3.25 (dd, J1 = 16.3 Hz, J2 = 1.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 149.30, 134.71, 134.50, 133.91,
133.60, 131.73, 130.24, 130.21, 129.60, 129.25, 128.87, 127.98,
127.47, 126.49, 125.67, 125.16, 122.96, 122.78, 36.06, 33.61.
HRMS (ESI): m/z calcd for C16H12FNO2 + Na (M + Na+): 292.0744;
found: 292.0750.
3g
HRMS (ESI): m/z calcd for C20H15NO2 + Na (M + Na)+: 324.0995;
found: 324.0981.
Reaction was carried out on a 10 mmol scale; yield: 1.65 g (52%);
yellow crystalline solid; mp 123.7–124.7 °C; Rf = 0.2 (5% EtOAc–
hexanes).
IR (ATR): 1641, 1499, 1454, 1323, 1267 cm–1.
3c
Reaction was carried out on a 20 mmol scale; yield: 3.77 g (67%);
1H NMR (400 MHz, CDCl3): δ = 8.24 (s, 1 H), 7.72 (d, J1 = 7.7 Hz,
1 H), 7.51–7.46 (m, 1 H), 7.38–7.33 (m, 2 H), 7.27 (dt, J1 = 21.0 Hz,
J2 = 7.6 Hz, 3 H), 7.08 (dd, J1 = 5.4 Hz, J2 = 3.3 Hz, 1 H), 6.98 (d,
yellow oil; Rf = 0.15 (5% EtOAc–hexanes).
IR (thin film): 1549, 1508, 1454, 1329, 1306, 1248, 1179, 1032
cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1719–1729

1726
C. Keene, L. Kürti
FEATURE ARTICLE
J1 = 7.7 Hz, 1 H), 5.0 (d, J1 = 8 Hz, 1 H), 3.66 (dd, J1 = 16.7 Hz,
J2 = 9.3 Hz, 1 H), 3.12 (d, J1 = 16 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 149.09, 138.11, 133.97, 133.60,
133.58, 132.06, 131.97, 130.17, 129.50, 128.85, 127.66, 127.33,
127.19, 126.88 (q, J1 = 5.9 Hz), 36.71, 34.20, 29.64.
3l
Reaction was carried out with 1 (10 mmol) and nitrostyrene 2l (5
mmol); yield: 891 mg (42%); yellow solid; mp 225–245 °C;
Rf = 0.25 (10% EtOAc–hexanes).
IR (ATR): 1508, 1314, 758 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.13–7.97 (m, 1 H), 7.50–7.19 [m,
5 (7) H], 7.17–7.03 (m, 4 H), 6.91 (d, J1 = 3.4 Hz, 1 H), 4.81 (dd,
J1 = 8.8 Hz, J2 = 6.4 Hz, 1 H), 4.56–4.35 (m, 2 H), 3.70–3.50 (m, 1
H), 3.19–2.99 (m, 2 H), 1.31–0.95 [m, 6 (8) H].
13C NMR (100 MHz, CDCl3): δ = 149.67, 140.72, 140.65, 139.21,
139.15, 138.40, 136.04, 134.64, 134.61, 132.21, 132.14, 132.11,
131.85, 131.82, 131.79, 130.13, 130.10, 130.05, 129.63, 129.60,
129.57, 128.69, 128.02, 128.00, 127.73, 127.71, 127.59, 127.46,
127.43, 127.40, 127.27, 127.24, 127.17, 127.12, 127.04, 57.01,
51.00, 45.14, 37.78, 37.71, 37.64, 36.77, 36.68, 30.07, 30.04, 29.98.
HRMS (ESI): m/z calcd for C17H12F3NO2 + Na (M + Na)+:
342.0712; found: 342.0697.
3h
Reaction was carried out on a 25 mmol scale; yield: 2.06 g (56%);
yellow crystalline solid; mp 91.0–93.5 °C; Rf = 0.2 (5% EtOAc–
hexanes).
IR (ATR): 1692, 1643, 1599, 1523, 1495, 1355, 1312, 1186 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 1 H), 8.00–7.88 (m, 1 H),
7.47 (dd, J1 = 7.2 Hz, J2 = 1.9 Hz, 1 H), 7.41–7.28 (m, 4 H), 7.14 (d,
J1 = 7.0 Hz, 1 H), 7.01–6.96 (m, 1 H), 5.17 (d, J1 = 9.5 Hz, 1 H),
3.74 (dd, J1 = 16.9 Hz, J2 = 9.4 Hz, 1 H), 3.30 (d, J1 = 17.0 Hz, 1 H).
HRMS (ESI): m/z calcd for C26H20N2O4 + Na (M + Na)+: 447.1315;
found: 447.1326.
13C NMR (100 MHz, CDCl3): δ = 148.47, 134.28, 134.23, 134.02,
134.00, 133.16, 132.33, 130.43, 129.37, 128.93, 128.27, 127.86,
127.80, 125.39, 36.02, 33.25.
HRMS (ESI): m/z calcd for C16H12N2O4 + Na (M + Na+): 319.0689:
found: 319.0677.
Radical Bromination of Cyclic Nitrostyrenes 3 To Form 3-Sub-
stituted 2-Nitronaphthalenes 4a–l; General Procedure
A 100 mL round-bottom flask, equipped with a magnetic stir bar,
was charged with the respective cyclic nitrostyrene 3 (10 mmol, 1
equiv), benzoyl peroxide (370 mg, 15 mol%), NBS (3.03 g, 17
mmol, 1.7 equiv), and 1,2-dichloroethane (67 mL). The resulting
solution was then kept at reflux for the indicated amount of time
(Table 2). Once the starting material was consumed, the reaction
mixture was cooled to r.t., diluted with CH2Cl2 (60 mL), and poured
into a separatory funnel. Next, 20% aq Na2S2O3 (100 mL) was add-
ed to neutralize the Br2 generated during the reaction. The aqueous
phase was then extracted with CH2Cl2 (3 × 100 mL) and the com-
bined organic layers were dried (MgSO4). The solvent was removed
in vacuo and the crude product was purified by column chromatog-
raphy with EtOAc–hexanes as eluent.
3i
Reaction was carried out on a 20 mmol scale; yield: 2.33 g (54%);
yellow oil; Rf = 0.35 (5% EtOAc–hexanes).
IR (thin film): 1547, 1514, 1454, 1366, 1302 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.90 (s, 1 H), 7.35–7.28 (m, 3 H),
7.26–7.19 (m, 2 H), 3.23–3.15 (m, 2 H), 3.11–3.03 (m, 1 H), 1.85
(td, J1 = 6.9 Hz, J2 = 5.9 Hz, 1 H), 0.92 (d, J1 = 6.9 Hz, 3 H), 0.76
(d, J1 = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.17, 136.47, 131.33, 131.30,
129.86, 129.80, 127.92, 127.06, 37.78, 30.63, 30.13, 20.24, 19.17.
4a
Reaction was carried out on a 20 mmol scale; yield: 4.98 g (99%);
3j
yellow solid; mp 90.0–93.5 °C; Rf = 0.22 (5% EtOAc–hexanes).
IR (ATR): 1595, 1522, 1501, 1450, 1348, 1315, 895 cm–1.
Reaction was carried out on a 20 mmol scale; yield: 2.45 g (57%);
yellow crystalline solid; mp 57.9–59.3 °C; Rf = 0.35 (5% EtOAc–
hexanes).
1H NMR (400 MHz, CDCl3): δ = 8.42 (s, 1 H), 7.98 (dd, J1 = 8.2 Hz,
J2 = 1.4 Hz, 1 H), 7.91 (dd, J1 = 8.2 Hz, J2 = 1.4 Hz, 1 H), 7.88 (s, 1
H), 7.70–7.61 (m, 2 H), 7.51–7.40 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 147.35, 137.68, 134.26, 132.77,
131.25, 131.03, 129.32, 128.77, 128.55, 127.97, 127.89, 127.86,
127.80, 124.51.
IR (ATR): 1638, 1501, 1468, 1454, 1308, 1204 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.87 (s, 1 H), 7.33–7.25 (m, 2 H),
7.20 (dd, J1 = 13.2 Hz, J2 = 7.3 Hz, 2 H), 3.31–3.22 (m, 2 H), 3.15
(d, J = 15.5 Hz, 1 H), 0.78 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 150.40, 137.41, 131.84, 131.27,
129.87, 129.45, 127.32, 126.88, 39.85, 36.84, 30.76, 27.37.
HRMS (ESI): m/z calcd for C14H17NO2 + Na (M + Na)+: 254.1152;
found: 254.1138.
HRMS (ESI): m/z calcd for C16H11NO2 + Na (M + Na)+: 272.0682;
found: 272.0654.
4b
Reaction was carried out on a 7 mmol scale; yield: 2.07 g (99%);
3k
yellow solid; mp 144.5–155.4 °C; Rf = 0.22 (5% EtOAc–hexanes).
IR (ATR): 1528, 1501, 1423, 1366, 1333 cm–1.
Reaction was carried out with 1 (9 mmol) and pentafluoronitrosty-
rene 2k (6.83 mmol); yield: 1.13 g (57%); yellow crystalline solid;
mp 179.8–188.1 °C; Rf = 0.3 (15% EtOAc–hexanes).
1H NMR (400 MHz, CDCl3): δ = 8.68 (d, J1 = 11.1 Hz, 1 H), 8.37
(d, J1 = 8.5 Hz, 1 H), 8.08 (d, J1 = 7.4 Hz, 1 H), 7.96–7.85 (m, 3 H),
7.75–7.67 (m, 2 H), 7.64–7.37 (m, 4 H), 7.30 (d, J1 = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 147.74, 147.32, 136.46, 136.14,
135.86, 134.50, 134.47, 133.05, 132.48, 131.82, 131.78, 131.54,
131.46, 131.44, 130.59, 130.10, 129.82, 129.60, 129.33, 129.16,
129.08, 128.40, 128.38, 128.22, 127.99, 127.89, 127.87, 127.63,
127.36, 127.27, 126.67, 126.48, 126.46, 125.93, 125.49, 125.22,
125.07, 124.85, 124.78, 123.15.
IR (ATR): 1688, 1506, 1479, 1452, 1319, 1198, 1001 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.27 (s, 1 H), 8.08 (s, 1 H), 7.83
(dd, J1 = 7.6 Hz, J2 = 1.7 Hz, 1 H), 7.52–7.38 (m, 4 H), 7.33 (t,
J1 = 7.4 Hz, 1 H), 7.18 (d, J1 = 7.5 Hz, 1 H), 7.06 (d, J1 = 7.6 Hz, 1
H), 4.99 (dd, J1 = 9.7 Hz, J2 = 5.0 Hz, 1 H), 4.55 (s, 2 H), 3.60 (dd,
J1 = 16.8 Hz, J2 = 9.6 Hz, 1 H), 3.20 (dd, J1 = 16.8 Hz, J2 = 4.9 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 192.80, 145.85, 138.89, 134.18,
134.13, 134.12, 133.95, 133.93, 133.53, 132.08, 130.60, 129.65,
129.40, 127.75, 127.34, 34.94, 29.48, 25.10.
HRMS (ESI): m/z calcd for C20H13NO2 + Na (M + Na)+: 322.0839;
found: 322.0822.
HRMS (ESI): m/z calcd for C24H15F4NO3 + Na (M + Na)+:
464.0880; found: 464.0880.
4c
Reaction was carried out on a 10 mmol scale; yield: 2.07 g (74%);
yellow solid; mp 115.0–116.0 °C; Rf = 0.2 (5% EtOAc–hexanes).
Synthesis 2013, 45, 1719–1729
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Regiospecific Synthesis of 3-Substituted 2-Nitronaphthalenes
1727
IR (ATR): 1520, 1495, 1452, 1437, 1356, 1283, 1254, 1055 cm–1.
4i
Reaction was carried out on a 10 mmol scale; yield: 2.06 g (96%);
1H NMR (400 MHz, CDCl3): δ = 8.76 (s, 1 H), 8.13 (d, J1 = 2.3 Hz,
1 H), 8.09–8.04 (m, 1 H), 7.97–7.93 (m, 1 H), 7.69–7.62 (m, 3 H),
7.40 (dd, J1 = 8.4, J2 = 2.2 Hz, 1 H), 7.06 (d, J1 = 8.4 Hz, 1 H), 4.00
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 155.85, 144.70, 140.47, 134.38,
134.15, 132.50, 132.19, 130.47, 129.94, 127.81, 126.09, 123.91,
119.82, 111.79, 56.35.
yellow solid; mp 68.3–73.4 °C; Rf = 0.35 (5% EtOAc–hexanes).
IR (ATR): 1524 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.26 (s, 1 H), 7.93–7.83 (m, 3 H),
7.66–7.50 (m, 2 H), 3.55 (td, J1 = 6.8 Hz, J2 = 0.6 Hz, 1 H), 1.39 (d,
J1 = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 148.52, 138.84, 134.76, 130.45,
128.82, 128.57, 127.53, 127.10, 126.63, 124.04, 28.52, 23.87.
4d
Reaction was carried out on a 6.5 mmol scale; yield: 2.16 g (98%);
yellow crystalline solid; mp 120.6–125.4 °C; Rf = 0.15 (10%
EtOAc–hexanes).
IR (ATR): 1530, 1472, 1441, 1408, 1372, 1352, 1086, 1005 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.80 (s, 1 H), 8.06 (d, J1 = 7.9 Hz,
1 H), 7.92 (d, J1 = 8.0 Hz, 1 H), 7.73–7.63 (m, 3 H), 4.01 (s, 3 H),
3.95 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 150.76, 147.10, 145.24, 135.98,
134.84, 131.98, 131.95, 131.63, 129.76, 129.39, 128.29, 128.01,
125.62, 113.93, 61.31, 61.04.
4j
Reaction was carried out on a 9 mmol scale; yield: 1.75 g, 85%; yel-
low solid; mp 73.8–75.0 °C; Rf = 0.35 (5% EtOAc–hexanes).
IR (ATR): 1630, 1603, 1526, 1499, 1329 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.81 (s, 1 H), 8.24 (d, J1 = 9.1 Hz,
1 H), 8.04 (d, J1 = 8.1 Hz, 1 H), 7.96 (t, J1 = 8.0 Hz, 2 H), 7.67
(dddd, J1 = 26.5 Hz, J2 = 8.3 Hz, J3 = 7.0 Hz, J4 = 1.4 Hz, 2 H), 1.50
(s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 145.35, 135.70, 131.79, 129.87,
129.64, 129.41, 127.89, 127.82, 124.50, 119.12, 35.68, 30.89.
4f
4k
Reaction was carried out on a 3 mmol scale; yield: 770 mg (96%);
Reaction was carried out on a 0.6 mmol scale; yield: 87 mg (32%);
yellow solid; mp 178.3–192.5 °C; Rf = 0.35 (15% EtOAc–hexanes).
IR (ATR): 1688, 1528, 1479, 1325, 1290, 995 cm–1.
yellow solid; mp 118.8–120.0 °C; Rf = 0.27 (10% EtOAc–hexanes).
IR (ATR): 1638, 1504, 1450, 1331, 1308, 1223 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.41 (s, 1 H), 7.97 (d, J1 = 8.0 Hz,
1 H), 7.91 (d, J1 = 8.0 Hz, 1 H), 7.83 (s, 1 H), 7.72–7.61 (m, 2 H),
7.37 (dd, J1 = 8.5 Hz, J2 = 5.4 Hz, 2 H), 7.14 (t, J1 = 8.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 162.56 (d, J1 = 247.6 Hz), 147.23,
134.27, 133.75 (d, J3 = 3.5 Hz), 131.77, 131.32, 131.15, 129.77 (d,
J3 = 8.2 Hz), 129.51, 128.85, 127.97, 127.88, 124.68 (d, J4 = 2.0
Hz), 115.59 (d, J2 = 21.7 Hz).
1H NMR (400 MHz, CDCl3): δ = 10.32 (s, 1 H), 8.78 (s, 1 H), 8.15–
8.04 (m, 3 H), 7.95 (d, J1 = 6.9 Hz, 3 H), 7.88 (dd, J1 = 7.6 Hz,
J2 = 1.6 Hz, 1 H), 7.78–7.69 (m, 3 H), 7.64–7.35 (m, 6 H), 7.18 (d,
J1 = 7.4 Hz, 1 H), 4.70 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 192.93, 171.92, 145.58, 138.90,
134.43, 134.12, 134.03, 133.73, 133.54, 133.40, 132.00, 130.28,
130.11, 129.52, 129.45, 129.21, 129.01, 128.41, 128.12, 127.70,
127.37, 126.35, 25.40.
4g
Reaction was carried out on a 1 mmol scale; yield: 301 mg (95%);
yellow crystalline solid; mp 78.0–80.0 °C; Rf = 0.25 (5% EtOAc–
hexanes).
HRMS (ESI): m/z calcd for C24H13F4NO3 + Na (M + Na)+:
462.0727; found: 462.0724.
Cyclic Nitroalkane 5
IR (ATR): 1759, 1601, 1526, 1504, 1337, 1313, 1167 cm–1.
To a 50 mL round-bottom flask, equipped with a magnetic stir bar
and an internal thermocouple, were added NaBH4 (645 mg, 4.42
equiv), EtOH (4 mL), and THF (5 mL). Next a solution of 3a (970
mg, 3.86 mmol, 1 equiv) in THF (8 mL) was added dropwise over
a period of 15 min. During the addition, an internal temperature of
35 °C was maintained. After the addition was complete, the reaction
was heated to 50 °C for 5 h. The reaction mixture was then diluted
with ice water (10 mL) and quenched with 50% AcOH–H2O (2.3
mL). Next CH2Cl2 (70 mL) was added, the layers separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 50 mL). The com-
bined organic phases were dried (MgSO4), filtered, and the solvent
was removed in vacuo. The crude product was purified by column
chromatography using 3% EtOAc–hexanes as eluent; yield: 505 mg
(52%); white solid; mp 94.6–96.7 °C; Rf = 0.2 (5% EtOAc–
hexanes).
1H NMR (400 MHz, CDCl3): δ = 8.73 (s, 1 H), 8.12–8.03 (m, 2 H),
7.91 (d, J1 = 8.1 Hz, 1 H), 7.82–7.77 (m, 2 H), 7.74–7.59 (m, 4 H),
7.53 (dt, J1 = 11.7 Hz, J2 = 7.7 Hz, 2 H), 7.39–7.36 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.02, 145.94, 137.23 (q,
J1 = 2.0 Hz), 134.26, 134.15, 131.83, 131.54, 131.41, 130.91,
130.23, 129.93, 129.73, 129.28, 128.82, 128.23, 127.98, 127.93,
126.01 (q, J2 = 5.1 Hz), 125.36.
HRMS (ESI): m/z calcd for for C17H10F3NO2 + Na (M + Na)+:
340.0556; found: 340.0531.
4h
Reaction was carried out on a 4.5 mmol scale; yield: 1.27 g (95%);
yellow crystalline solid; mp 136.3–137.9 °C; Rf = 0.22 (5%
EtOAc–hexanes).
IR (ATR): 3028, 2917, 2360, 1543, 1374 cm–1.
IR (ATR): 1599, 1517, 1500, 1487, 1346, 1308 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.24 (m, 6 H), 7.22–7.19 (m,
1 H), 7.14–7.10 (m, 2 H), 5.09 (ddd, J1 = 8.3 Hz, J2 = 5.5 Hz, J3 =
3.9 Hz, 1 H), 3.93 (td, J1 = 5.9, J2 = 3.9 Hz, 1 H), 3.43 (d, J1 = 6.0
Hz, 2 H), 3.32 (qd, J1 = 17.1 Hz, J2 = 6.9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 138.45, 134.21, 131.65, 128.97,
128.59, 128.52, 127.76, 127.65, 126.86, 126.49, 84.75, 77.32,
77.00, 76.68, 42.18, 32.71, 29.82.
1H NMR (400 MHz, CDCl3): δ = 8.82 (s, 1 H), 8.23 (d, J1 = 8.2 Hz,
1 H), 8.07 (d, J1 = 7.8 Hz, 1 H), 7.88 (d, J1 = 7.9 Hz, 1 H), 7.74–7.66
(m, 4 H), 7.61 (t, J1 = 7.8 Hz, 1 H), 7.43 (d, J1 = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 147.26, 145.42, 134.79, 134.65,
133.44, 131.63, 131.53, 130.41, 130.26, 130.13, 129.52, 128.96,
128.32, 127.82, 125.81, 124.74.
HRMS (ESI): m/z calcd for C16H10N2O4 + Na (M + Na)+: 317.0533;
found: 317.0510.
HRMS (ESI): m/z calcd for C16H15NO2 + Na (M + Na)+: 276.0995;
found: 276.0985.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1719–1729

1728
C. Keene, L. Kürti
FEATURE ARTICLE
Cyclic Amphetamine Analogue 6
8 as a pink oil, which solidified upon standing overnight; yield: 1.3
g (90%); Rf = 0.27 (10% EtOAc–hexanes).
IR (thin film): 1638, 1609, 1504, 1493, 466, 905, 727 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J1 = 8.2 Hz, 1 H), 7.67–
7.65 (m, 2 H), 7.60–7.51 (m, 4 H), 7.47–7.41 (m, 2 H), 7.31–7.25
(m, 1 H), 7.10 (s, 1 H), 3.92 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 142.09, 138.97, 134.34, 130.68,
129.42, 129.19, 128.76, 127.93, 127.68, 127.52, 126.24, 125.31,
122.55, 108.87.
A flame-dried 50 mL round-bottom flask, equipped with magnetic
stir bar, was charged with LiAlH4 (244 mg, 6.42 mmol, 2 equiv) and
anhyd THF (8 mL). The resulting suspension was then cooled to
0 °C. Next, a solution of 3a (0.807 g, 3.21 mmol, 1 equiv) in anhyd
THF (8 mL) was added dropwise. After the addition was complete,
the reaction mixture was heated at reflux for 12 h after which it was
allowed to cool first to r.t., then to 0 °C in an ice bath. Careful
quenching was performed by first adding H2O (0.244 mL) drop-
wise, followed by 15% aq NaOH (0.244 mL), and more H2O (0.73
mL). The resulting slurry was allowed to warm to r.t. and stirred for
an additional 30 min. The pasty-white mixture was then filtered
over Celite to give a yellow-tinted organic phase. The Celite was
then washed sequentially with EtOAc (120 mL) and CH2Cl2 (120
mL). The combined organic layers were then evaporated and
reagent-grade i-PrOH (5 mL) was added to the residue. Next, a
slight excess of concd HCl (37%, 0.27 mL) was also added, causing
heat evolution. Upon cooling, the HCl salt of 6 begins to precipitate
out of solution. Upon dilution with Et2O (10 mL) more solid precip-
itated. The solid was filtered, washed with Et2O (50 mL), dried in
vacuo to afford the HCl salt of 6; yield: 534 mg (64%); white solid;
Rf = 0.2 (40% EtOAc–hexanes).
HRMS (ESI): m/z calcd for C16H13N (M + H)+: 220.1121; found:
220.1111.
Diazonium Tetrafluoroborate 9
A 100 mL round-bottom flask, equipped with magnetic stir bar, was
charged with 3-phenyl-2-aminonaphthalene (7; 856 mg, 1 equiv)
and CH2Cl2 (39 mL). The solution was then cooled to 0 °C in an ice
bath and stirred for 10 min. Next, Et2O·BF3 (0.578 mL, 4.68 mmol,
1.2 equiv) was added dropwise, followed by the dropwise addition
of neat tert-butyl nitrite (0.774 mL, 1.5 equiv) upon which the color
of the reaction mixture became brown. The mixture was then al-
lowed to warm to r.t., the diazonium tetrafluoroborate salt was fil-
tered through a frit funnel, and washed with CH2Cl2 (5 mL) to
afford of 9; yield: 1.12 g (90%); yellow solid.
1H NMR (400 MHz, DMSO-d6): δ = 8.34 (s, 3 H), 7.51–7.14 (m, 9
H), 3.84 (br s, 1 H), 3.67 (br s, 1 H), 3.41–3.30 (m, 1 H), 3.18 (ddd,
J1 = 21.8 Hz, J2 = 17.1 Hz, J3 = 5.3 Hz, 2 H), 2.88–2.77 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 140.28, 135.60, 133.35,
129.92, 129.62, 129.52, 129.30, 128.17, 127.56, 127.01, 50.21,
32.67, 31.29, 26.44.
3-Phenyl-2-naphthol (10)
A 10 mL round-bottom flask, equipped with magnetic stir bar and
gas outlet, was charged with the diazonium salt 9 (318 mg, 1 mmol,
1 equiv), THF (1.6 mL), and H2O (1.6 mL). The reaction mixture
was then heated at 60 °C for 1 h until gas evolution ceased. The re-
sulting red solution was diluted with CHCl3 (5 mL) and transferred
into a separatory funnel with H2O (30 mL). The aqueous phase was
then extracted with CHCl3 (3 × 15 mL), the combined organic lay-
ers were dried (MgSO4), filtered, and the solvent was removed in
vacuo. Elution with 10% EtOAc–hexanes gave 9; yield: 102 mg
(46%); white solid; mp 114.3–115.0 °C; Rf = 0.2 (10% EtOAc–
hexanes).
Fused 1,2,3-Triazole 7
A 10 mL round-bottom flask, equipped with magnetic stir bar, was
sequentially charged with 3a (439 mg, 1.75 mmol, 1 equiv), DMSO
(3.5 mL), and NaN3 (227 mg, 3.5 mmol, 2 equiv). The reaction mix-
ture was then heated at 90 °C for 2 h until all the starting material
was consumed (progress was followed by TLC analysis). The flask
was allowed to cool to r.t. before adding H2O (3 mL) dropwise. The
biphasic mixture was then extracted in a separatory funnel with
CH2Cl2 (3 × 30 mL). The combined organic phases were dried
(MgSO4), filtered, and the solvent was removed in vacuo. The crude
product was purified by column chromatography. Elution with 30%
EtOAc–hexanes afforded 7; yield: 415 mg (96%); crystalline white
solid; mp 200–205 °C; Rf = 0.4 (30% EtOAc–hexanes).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J1 = 8.3 Hz, 1 H), 7.79–
7.74 (m, 2 H), 7.62–7.59 (m, 2 H), 7.55 (t, J1 = 8.5 Hz, 2 H), 7.48
(ddd, J1 = 8.3 Hz, J2 = 6.9 Hz, J3 = 1.4 Hz, 2 H), 7.40–7.35 (m, 2 H),
5.40 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 150.69, 136.80, 134.22, 130.39,
129.52, 129.27, 129.16, 128.84, 128.09, 127.72, 126.45, 126.18,
123.84, 110.17.
1H NMR (400 MHz, CDCl3): δ = 13.78 (br s, 1 H, NH), 7.91 (d,
J1 = 7.4 Hz, 1 H), 7.35–7.17 (m, 8 H), 4.40 (dd, J1 = 9.0 Hz, J2 = 6.7
Hz, 1 H), 3.40–3.20 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 141.55, 135.06, 128.55, 128.48,
128.41, 127.57, 127.31, 127.04, 126.95, 122.95, 38.20, 37.95.
HRMS (ESI): m/z calcd for C16H13N3 + Na (M + H)+: 248.1182;
found: 248.1182.
3,3′-Diphenyl-BINAM (11)
A 50 mL round-bottom flask was charged with a finely ground paste
of 8 (219 mg, 1 mmol, 1 equiv) and FeCl3·6H2O (730 mg, 4.5 mmol,
4.5 equiv) that was prepared with a mortar and pestle. Next, H2O
(0.5 mL) was added, the flask was sealed with a septum, and heated
at 90 °C for 72 h, after which time it was cooled to r.t. and then
CHCl3 (30 mL) was added. The contents of the flask were then
transferred into a separatory funnel along with H2O (30 mL) and the
aqueous phase was washed with CHCl3 (3 × 40 mL). The combined
organic layers were dried (MgSO4) and the solvent was removed in
vacuo. The crude material was purified by column chromatography
using 4% EtOAc–hexanes to afford 11; yield: 82 mg (38%); yellow
solid; Rf = 0.2 (10% EtOAc–hexanes).
3-Phenyl-2-Aminonaphthalene (8)
A flame-dried 100 mL round-bottom flask, equipped with a mag-
netic stir bar, was charged with 10% Pd/C (1.3 g, 0.987 mmol, 15
mol%) and EtOAc (10 mL) that was injected slowly along the inner
wall of the flask. Next, the solution of 3-phenyl-2-nitronaphthalene
(4a; 1.64 g, 6.58 mmol, 1 equiv) in CH2Cl2 (10 mL) was added. The
reaction mixture was then purged with H2 gas by means of bubbling
it through the solution from a balloon for 15 min. Next, a fresh bal-
loon of H2 gas was placed atop the flask. The reaction mixture was
allowed to stir for 10 h at which point the starting material was no
longer detected by TLC analysis (eluent: 10% EtOAc–hexanes).
The reaction mixture was then filtered through Celite and washed
with EtOAc (100 mL) and CH2Cl2 (100 mL). The combined organic
solvents were removed in vacuo and the residue was purified by col-
umn chromatography. Elution with 10% EtOAc–hexanes afforded
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J1 = 8.1 Hz, 1 H), 7.65 (t,
J1 = 4.2 Hz, 2 H), 7.60–7.49 (m, 3 H), 7.47–7.38 (m, 2 H), 7.30–
7.24 (m, 1 H), 7.09 (s, 1 H), 3.92 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 142.10, 138.99, 134.36, 130.71,
129.44, 129.21, 128.78, 127.95, 127.70, 127.54, 126.25, 125.32,
122.57, 108.89.
HRMS (ESI): m/z calcd for C32H24N2 + Na (M + Na)+: 459.1832;
found: 459.1815.
Synthesis 2013, 45, 1719–1729
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Acknowledgment
Regiospecific Synthesis of 3-Substituted 2-Nitronaphthalenes
1729
(c) Chen, L.-Y.; Li, S.-R.; Chen, P.-Y.; Chang, H.-C.; Wang,
T.-P.; Tsai, I.-L.; Wang, E.-C. ARKIVOC 2010, (xi), 64.
(d) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209.
(e) Girard, S. A.; Hu, X.; Knauber, T.; Zhou, F.; Simon, M.-
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Ed. 2012, 51, 7537.
L.K. gratefully acknowledges the generous financial support of the
UT Southwestern Endowed Scholars in Biomedical Research Pro-
gram (W.W. Caruth Jr., Endowed Scholarship in Biomedical Re-
search), the Robert A. Welch Foundation (Grant I-1764), the ACS
Petroleum Research Fund (Doctoral New Investigator Grant 51707-
DNI1), and the American Cancer Society & Simmons Cancer Cen-
ter Institutional Research Grant (New Investigator Award in Cancer
Research, ACS-IRG 02-196).
(10) Bhattacharjya, A.; Mukhopadhyay, R.; Pakrashi, S. C.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1719–1729