Cu-catalyzed selective mono-N-pyridylation: Direct access to 2-aminoDMAP/sulfonamides as bifunctional organocatalysts

Article abstract of DOI:10.1021/jo302713b

Direct and selective mono-N-pyridylation of trans-(R,R)-cyclohexane-1,2- diamine is described here. Facile preparation of a novel chiral 2-aminoDMAP core catalaphore via Cu catalysis has led to the development of various sulfonamide/2-aminoDMAPs as bifunctional acid/base organocatalysts (most in two steps overall), which have been shown to very effectively promote asymmetric conjugate addition of acetylacetone to trans-β-nitroolefins with good to excellent yields (87-93%) and enantioselectivites (up to 99%).

Full text of DOI:10.1021/jo302713b

Article
pubs.acs.org/joc
Cu-Catalyzed Selective Mono‑N‑pyridylation: Direct Access to
2‑AminoDMAP/Sulfonamides as Bifunctional Organocatalysts
Murat Isik† and Cihangir Tanyeli*
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
S
* Supporting Information
ABSTRACT: Direct and selective mono-N-pyridylation of
trans-(R,R)-cyclohexane-1,2-diamine is described here. Facile
preparation of a novel chiral 2-aminoDMAP core catalaphore
via Cu catalysis has led to the development of various
sulfonamide/2-aminoDMAPs as bifunctional acid/base orga-
nocatalysts (most in two steps overall), which have been
shown to very effectively promote asymmetric conjugate
addition of acetylacetone to trans-β-nitroolefins with good to
excellent yields (87−93%) and enantioselectivites (up to
99%).
Herein, we have anticipated that the chiral 2-aminoDMAP14
1 derived from trans-cyclohexane-1,2-diamine could serve as a
versatile Lewis basic catalaphore, and introduction of various H-
offer unique reactivity and versatility as Lewis base catalysts
bond donor entities via modification of the remaining primary
in a wide array of reactions where some prominent examples
amine might lead to discovery of novel reactivities in the
include kinetic resolution (KR) of sec-alcohols and sec-amines
context of bifunctional acid/base catalyst development (Figure
and Steglich rearrangement.1 Although numerous chiral
1).
INTRODUCTION
■
Chiral 4-(N,N-dimethylamino)pyridine (DMAP) analogues
variants have been reported to date, due to challenges for
effective chirality introduction to the DMAP unit (on account
of its highly symmetrical nature), synthetic protocols often
require multiple steps, and more practical and rational designs
still remain elusive.2 The catalytic role of chiral DMAPs resides
mainly in their nucleophilic character particularly for KR of sec-
alcohols.1 However, a planar chiral 4-dialkylaminopyridine
developed by Fu is shown to effectively catalyze the addition of
nitrogen nucleophiles to prochiral ketenes, wherein the DMAP
unit acts as a Brønsted base.3 Following their ground-breaking
Figure 1. Catalyst design rationale.
work, DMAP-pyrrolidine hybrids are reported to be very
effective chiral catalysts in Michael reaction in a work by
In principle, it was thought that 2-N-alkylamino and 4-
dimethylamino disubstituted chiral pyridine 1 might act as both
Kotsuki,4 and this unequivocally reveals the Brønsted basic
nature of DMAP as well. More interestingly, a recent report by
Wulff5 clearly demonstrates the dramatic impact of superior
base (DMAP over triaklylamines6) in bifunctional organo-
catalyst design.7 Remarkably important is Johnston’s both C1-
and C2-symmetric bisamidine (BAM) type catalysts,8 which
highlight fruitful emergence of relatively unexplored 2-amino-
pyridine chemistry in asymmetric organocatalysis.8,9 trans-
Cyclohexane-1,2-diamine, arguably the most frequently ad-
dressed vicinal chiral diamine, has proven its broad utility in a
diverse array of catalyst systems (from salen type transition
metal complexes10 to bifunctional acid/base organocatalysts11)
as a “privileged”12 chiral catalyst backbone. Consequently, there
is a significant demand to evolve novel practical methodologies
targeting direct mono-N-functionalization of such C2-sym-
metrical diamines.13
Brønsted base and nucleophile, due to two electron-donor
nitrogens on the pyridine ring rendering it highly electron-rich,
which may amplify the scope of the reactions to be catalyzed.
RESULTS AND DISCUSSION
■
To afford compound 1, we initially explored the possibility of
Pd-catalyzed Buchwald−Hartwig N-arylation15 of the (1R,2R)-
cyclohexane-1,2-diamine with 2-haloDMAPs 2a,b.16 Of the
various conditions investigated, Wulff’s coupling protocol was
adapted first; however, no trace of target compound 1 was
observed.5,17 In all of our efforts, direct mono-N-pyridylation
attempts by Pd-catalysis failed.18
Received: December 13, 2012
Published: January 18, 2013
© 2013 American Chemical Society
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Realizing unsatisfactory results with palladium chemistry, we
turned our attention to a copper-catalyzed modified Ullmann
coupling reaction that is generally complementary to the former
comprising air-sensitive and high-priced bis-phosphine ligands.
In a miscellaneous screening of varied nucleophiles for Cu-
catalyzed C−N bond-forming reactions, Buchwald observed a
selective mono-N-arylated product in moderate yield while
using trans-cyclohexane-1,2-diamine ligand as the nucleophile
and p-bromotoluene as the electrophile.19 Inspired by their
work, we initiated our copper catalysis studies (Table 1).
speculative mechanism for the formation of products 1 and 3
in parallel with the previously published similar work in the
literature.22
Scheme 1. Putative Operating Catalytic Cycle
Table 1. Optimization Studies for Cu-Catalyzed Selective
a
Mono-N-pyridylation
b
yields (%)
entry
base
2
CuX
1
3
c
The scenario is presumed to start with the chelation of the
(1R,2R)-cyclohexane-1,2-diamine with the CuBr to form
activated copper complex 4, and subsequent oxidative addition
of 2-bromoDMAP 2b is thought to generate unstable
pentacoordinate reactive intermediate 5. In the presence of a
base, intermediate 5 is speculated to undergo reductive
elimination to afford 1, which is exchanged with the sterically
less demanding diamine ligand. Then the catalytically active
copper species 4 would be ready to operate in the forthcoming
cycle. Furthermore, a possible speculation for the generally
observed selectivity of 1 over 3 would be as follows:
Competitive ligation of the product 1 and diamine substrate
to the copper is supposed to result in favor of the sterically less
demanding diamine, since the DMAP unit of 1, upon
coordination to the copper metal, might eradicate the
nucleophilicity of the remaining primary amine. As a result,
further arylation of 1 is speculated to proceed more slowly than
the competing free ligand.
In his recent reports, Johnston observed consistently higher
stereodifferentiation by the C1-symmetric BAM catalysts over
the C2-symmetric ones. Indeed, synthesis of the former calls for
the selective mono-N-heteroarylation of trans-cyclohexane-1,2-
diamine for practical reasons.8 For this purpose, the value of the
mono-N-heteroarylative process that we developed herein was
clearly shown to be a high-yielding shortcut method for the
formal synthesis of Johnston’s C1-symmetric BAM catalysts
(Scheme 2).
1
K3PO4
K3PO4
K2CO3
Cs2CO3
NaOtBu
KOtBu
K3PO4
K3PO4
K3PO4
K3PO4
2a/2b/2c
none
CuI
2
2b
2b
2b
2b
2b
2a
2c
2b
2b
56
40
53
9
16
23
16
2
3
CuI
4
CuI
5
CuI
6
CuI
27
17
26
60
58
4
7
CuI
4
8
CuI
32
6
9
CuBr
CuCl
10
8
a
Reaction conditions: trans-cyclohexane-1,2-diamine (1.2 mmol), 2a−
c (1.0 mmol), base (2.0 mmol), 20 mol % CuX, and 1 mL of 1,4-
dioxane were stirred at 110 °C for 24 h under Ar atm. Isolated yields.
Reaction was carried out in the absence of copper source with 2-
haloDMAPs (2a, 2b, and 2c); however no mono- or disubstituted
coupling products were observed.
b
c
Investigation of copper-free SNAr type reactions showed no
trace of coupling products 1 and 3 (entry 1, Table 1). To our
delight, we could isolate the target compound 1 in appreciable
yields using K3PO4 and Cs2CO3, through base screening
(K3PO4, K2CO3, Cs2CO3, NaOtBu, and KOtBu) experiments
(entries 2−6). Because of its much lower price and relatively
higher reactivity, tribasic potassium phosphate was chosen as
the base for further optimization studies. The effect of the
nature of the electrophile (2-haloDMAP 2a and 2c) was
investigated next (entries 7 and 8). 2a and 2c resulted in poorer
conversions, where the latter produced compound 320 as the
major product. Selectivity was considerably reduced (26% vs
32%) in the case of 2c, which proved to be a highly reactive
substrate for this transformation (entry 8).21 The effect of
copper source was also investigated as the final work to
optimize the yield of 1 (entries 9 and 10). Among the
copper(I) species (Cl, Br, and I), CuBr gave the best result
(entry 9). To the best of our knowledge, this is the first
successful example of direct and selective mono-N-hetero-
arylation of a vicinal diamine.18 Scheme 1 presents the
Successful synthesis of 2-aminoDMAP 1 readily in only one
step encouraged us to investigate the catalytic potential of this
basic catalaphore unit in pursuit of efficient bifunctional acid/
base organocatalysts.23 Sulfonamides were chosen to chaperon
2-aminoDMAP base as the H-bond donor counterpart, due to
their ready availability, modular tunability, and recent successful
reports claiming the advantageous case of sulfonamides and
sulfinylureas over commonly employed thioureas.24 In this
regard, 10 examples of 2-aminoDMAP/Sulfonamides 7a−j
were designed and prepared by following the systematic
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Scheme 2. Formal Synthesis of Johnston’s BAM Catalyst
a
structural elaborations having both steric and electronic bases
presented in Scheme 3.
Table 2. Evaluation of 2-AminoDMAP/Sulfonamides 7a−j
Scheme 3. Systematicity in the Design of 2-AminoDMAP/
Sulfonamides 7a−j
b
entry
catalyst
time (h)
yield (%)
ee (%)
1
7a
7b
7c
7d
7e
7f
48
192
52
48
44
46
48
50
64
72
30
90
60
96
144
72
90
90
91
89
89
91
89
88
90
89
90
91
88
89
89
89
62
61
60
74
84
76
88
28
50
57
82
89
90
92
93
92
2
3
4
5
6
7
7g
7h
7i
8
9
10
7j
c
11
7g
7g
7g
7g
7g
7g
d
12
e
13
f
14
15 ,
f g
16 ,
f h
a
b
Reactions were carried out in 0.2 M concentration of 8. Time for
c
d
complete conversion. 0.4 M concentration of 8. 0.1 M concentration
of 8. Reaction was carried out at 0 °C. Reaction was carried out at
−10 °C. 5 mol % cat. loading. 20 mol % cat. loading.
e
f
g
h
Developed catalysts were screened with the conjugate
addition of acetylacetone to trans-β-nitrostyrene serving as
the testing ground for bifunctional organocatalysis (Table
2).23,25 Distinct acidities of 7a and 7b had no impact on
enantioselectivity and produced moderate results (entries 1 and
2). Steric demand of catalysts 7c−e was clearly observed by a
parallel increase in selectivity (60%, 74%, 84% ee’s, respectively;
entries 3−5). Further, concomitant modulation of steric bulk
and acidity was devised by insertion of a nitro group to the meta
positions of the best acting candidates 7d and 7e. Both 7f and
7g were observed to induce slightly higher selectivities (entries
4 and 5 vs entries 6 and 7). Catalysts 7h and 7i, offered to
examine the effect of secondary chirality on the sulfonamide
unit, provided low selectivities. Catalyst 7j bearing an additional
phenolic proton gave significantly lower selectivity than all of
the other aromatic sulfonamides. Choosing 7g as the best
catalyst, the effects of solvent, molarity, temperature, and
catalyst loading were investigated as well to secure the optimal
working condition (entries 11−16). Of the screened solvents,
toluene proved to be the best one.17 Enantioselectivity
decreased at higher concentration (0.4 M) of substrates
(entry 11). Almost equal enantioselection (89% ee) was
observed at lower concentration (0.1 M); however, reaction
was sluggish at this time (entry 12). Selectivity was slighty
increased upon lowering the temperature to 0 °C and −10 °C
(90% and 92% ee; entries 13 and 14, respectively). It is worthy
to note that 7g tolerated well 5−20 mol % catalyst loadings
(entries 15 and 16).
With the optimized reaction condition in hand, the scope of
this enantioselective organocatalytic conjugate addition was
examined further by varying trans-β-nitroolefins. All the
reactions were conducted in toluene at 0 °C with 0.2 M
concentration of 11a−h. The results are summarized in Table
3.
Most of the conjugate addition products were obtained in
high to excellent yields (87−93%) and selectivities (75−99%
ee). It is noteworthy that the reaction worked very well with m-
and p-chloro-substituted trans-β-nitrostyrene derivatives 12c
and 12d with 97% and 99% ee, respectively. It appears that the
electronic nature of the aromatic rings of nitroolefins has little
effect on both reaction kinetics and stereoselection.
With these results in hand, a plausible transition state (TS)
model was proposed as in Figure 2 to account for the sense of
bifunctionality and enantioselectivity brought by 7g. According
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a
J values are given in hertz. Spin multiplicities are reported as the
following: s (singlet), bs (broad singlet), d (doublet), dd (doublet of
doublet), ddd (doublet of doublet of doublet), dt (doublet of triplet),
dq (doublet of quartet), t (triplet), q (quartet), sept (septet), m
(multiplet). Polarimetric measurements were made by the use of a
polarimeter and reported as follows [α]3D1 (c in g per 100 mL, solvent).
Enantiomeric excess (ee) values of chiral adducts were detected by a
HPLC system using Daicell AS-H chiral column (0.46 cm ϕ × 25 cm),
AD-H chiral column (0.4 cm ϕ × 10 cm), and IA chiral column (0.46
cm ϕ × 25 cm). HRMS data were acquired on a time of flight (TOF)
mass spectrometer. IR spectra of all new compounds were obtained by
an IR spectrometer. Flash column chromatography (FCC) was
performed by using glass columns with a flash grade silica gel (230−
400 mesh). Reactions were monitored by thin layer chromatography
(TLC) using precoated silica gel plates, visualized by UV light and p-
anisaldehyde, ninhydrin, and potassium permanganate stains as
appropriate. All organic extracts were dehydrated over oven-dried
MgSO4 or K2CO3 and concentrated by using a rotary evaporator
before being subjected to FCC.
General Procedure for Cu-Catalyzed C−N Coupling Reac-
tions. An oven-dried resealable Schlenk tube was charged with CuBr
(29 mg, 0.2 mmol) and K3PO4 (424 mg, 2.0 mmol), evacuated, and
backfilled with argon thrice. (R,R)-Cyclohexane-1,2-diamine (137 mg,
1.20 mmol), 2-bromoDMAP (201 mg, 1.0 mmol) or 2-bromoquino-
line (208 mg, 1.0 mmol), and dioxane that was distilled over Na-
benzophenone under Ar atmosphere (1.0 mL) were added by Schlenk
line. The Schlenk tube was sealed, and the reaction mixture was stirred
at 110 °C for 24 h. The resulting green-blue suspension was allowed to
reach room temperature. Then 2 mL of water and 2 mL of conc
ammonia were added consecutively. The resulting Prussian blue
solution was extracted with dichloromethane thrice (3 × 25 mL). The
combined dichloromethane phase was dried with brine and MgSO4,
respectively. The filtrate was concentrated, and the residue was
purified by flash chromatography on silica gel using dichloromethane
that was saturated with conc aqueous ammonia to afford compounds 1
and 6 as pale brown solids.
Table 3. Substrate Scope of trans-β-Nitroolefins
b
c
entry
Ar
product
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
2-NO2-C6H4
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
2-thienyl
12a
12b
12c
12d
12e
12f
58
60
60
60
70
72
70
65
87
91
88
93
76
91
91
90
86
75
97
99
85
96
93
2-furyl
4-BnO-C6H4
2-MeO-C6H4
12g
12h
90
a
b
Reactions were carried out in 0.2 M concentration of 11a−h. Time
c
for complete conversion. Isolated chemical yields.
Figure 2. Plausible TS model−bifunctional activation mode.
Data for 1. Tan brown solid, 140 mg, 60% yield. Mp: 138−140 °C.
[α]3D1 = −55.0 (c 0.25, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 0.93−
1.09 (m, 1H), 1.09−1.43 (m, 3H), 1.65 (dd, J = 2.5, 10.0 Hz, 2H),
1.75 (bs, 2H), 1.85−1.95 (m, 1H), 1.97−2.07 (m, 1H), 2.41 (dt, J =
4.1, 10.4 Hz, 1H), 2.87 (s, 6H), 3.24 (dq, J = 4.0, 9.6 Hz, 1H), 4.15 (d,
J = 9.5 Hz, 1H), 5.53 (d, J = 2.2 Hz, 1H), 5.91 (dd, J = 2.3, 6.1 Hz,
1H), 7.69 (d, J = 6.1 Hz, 1H). 13C NMR (100.6 MHz, CDCl3) δ 25.1,
25.4, 32.9, 34.9, 39.2, 56.3, 58.4, 87.8, 99.2, 148.0, 156.1, 160.1. IR
(neat) 3321, 3254, 2922, 2854, 1599, 1527, 1495, 1444, 1265, 1145,
979, 964, 804. HRMS (ESI) calcd for C13H23N4 [M + H]+ 235.1923,
found 235.1918.
to this model, -NH of sulfonamide unit was be responsible for
acceptor alkene activation through hydrogen bonding with the
nitro group.24b,c For nucleophile activation, we propose two
hydrogen bonding sites available between 2-aminoDMAP unit
and the dicarbonyl after partial deprotonation.
CONCLUSIONS
■
To sum up, we have described successful direct and selective
mono-N-pyridylation of trans-cyclohexane-1,2-diamine for the
first time. Our C−N bond-forming protocol was found to
reduce the number of steps involved in the synthesis of
Johnston’s elegant BAM catalyst dramatically. Transforming
trans-cyclohexane-1,2-diamine to its monoamidine in one
straightforward step as in our present study would outpace
the protective C−N coupling strategies applied so far to that
end, at least partly due to time and cost effectiveness.
Systematically tuned catalyst 7g was shown to promote the
conjugate addition reaction of acetylacetone and various
nitroolefins very effectively with good to excellent yields
(87−93%) and with enantioselectivites up to 99%. Judicious
incorporation of novel H-bond donors to the chiral 2-
aminoDMAP 1 developed herein may give birth to more
practical and fruitful organocatalyst libraries for any asymmetric
reaction of interest. Current investigations directed along these
lines are in progress.
1
Data for 6. Tan brown solid, 144 mg, 60% yield. H NMR (400
MHz, CDCl3) δ 0.98−1.11 (m, 1H), 1.12−1.37 (m, 3H), 1.63 (dd, J =
3.7, 10.0 Hz, 2H), 1.79−2.12 (m, 4H), 2.43 (td, J = 4.0, 10.1 Hz, 1H),
3.64 (bs, 1H), 4.83 (bs, 1H), 6.59 (d, J = 8.9 Hz, 1H), 7.06−7.12 (m,
1H), 7.41 (ddd, J = 1.5, 7.0, 8.4 Hz, 1H), 7.44−7.48 (m, 1H), 7.54 (t, J
= 10.3 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H). 13C NMR (100.6 MHz,
70:30 CDCl3:CCl4) δ 25.1, 25.3, 32.9, 35.3, 56.3, 57.5, 111.6, 121.9,
123.5, 126.2, 127.3, 129.5, 137.2, 148.0, 157.2. HRMS (ESI) calcd for
C15H20N3 [M + H]+ 242.1657, found 242.1614.
General Procedure for Buchwald-Hartwig C−N Coupling
Reactions. In a Schlenk flask, (1R,2R)-cyclohexane-1,2-diamine or
mono-N-protected amine (1 mmol), 2-haloDMAP (2a,b) (1 mmol),
base (1.5 mmol), bisphosphine ligand (0.15 mmol), and Pd complex
(0.075 mmol) were mixed, and 8 mL of toluene (distilled over Na-
benzophenone under Ar atmosphere) was added under Ar atm. The
resulting mixture was refluxed for 60 h. At the end of the reaction, the
mixture was cooled to rt and transferred to a separatory funnel. The
organic phase was washed with 10 mL of water, and the separated
organic phase was dried over MgSO4 and filtered. The filtrate was
concentrated under vacuum. The dark residue was purified with flash
chromatography using 98:2 EtOAc/TEA (see “Table for Buchwald-
Hartwig C−N Coupling Reactions” in Supporting Information).
EXPERIMENTAL SECTION
■
1H NMR and 13C NMR spectra were recorded on a 400
spectrophotometer using CDCl3, CCl4, or d6-DMSO as the solvent.
Chemical shifts values are reported in ppm from tetramethylsilane, and
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Data for 14. In a Schlenk flask, mono-N-phthalolyl protected
amine 1326 (489 mg, 2 mmol), 2-bromoDMAP (402 mg, 2 mmol),
Cs2CO3 (978 mg, 3 mmol), BINAP (280 mg, 0.30 mmol), and
Pd(OAc)2 (34 mg, 0.15 mmol) were mixed, and 15 mL of toluene
(distilled over Na-benzophenone under Ar atmosphere) was added
under Ar atm. The resulting mixture was refluxed for 60 h. At the end
of the reaction, the mixture was cooled to rt and transferred to a
separatory funnel. The organic phase was washed with 20 mL of water,
and the separated organic phase was dried with MgSO4 and filtered.
The filtrate was concentrated under vacuum. The dark residue was
purified with flash chromatography using 98:2 EtOAc/TEA. As a
result, product 14 was obtained as a pale yellow solid (109 mg, 15%
2854, 1728, 1529, 1584, 1455, 1392, 1368, 1361, 1173, 1112, 563.
HRMS (ESI) calcd for C15H23N2O4S [M − H]− 327.1379, found
327.1402. Due to ambiguity in HRMS analysis of the parent
compound, it was converted to the corresponding sulfonamide by
following procedure: A 20 mL 1:1 DCM/ammonia (conc) solution of
2,4,6-triisopropyl-3-nitrobenzene-1-sulfonyl chloride (348 mg, 1
mmol) was vigorously stirred at rt for 2 h. The DCM phase was
dried over potassium carbonate, and the filtrate was concentrated
under vacuum. Corresponding sulfonamide product was characterized
by HRMS analysis without further purification.
General Procedure for the Preparation of 2-AminoDMAP/
Sulfonamides 7a−j. To a solution of (R,R) 2-aminoDMAP 1 (47
mg, 0.2 mmol) and triethylamine (22.2 mg, 30 μL, 0.22 mmol) in
CH2Cl2 (1 mL) was added sulfonyl chloride (0.2 mmol as solid or
liquid) at 0 °C. The mixture was brought to room temperature and
stirred for 1 h. The mixture was directly loaded on to a silica gel
column and eluted with EtOAc/TEA (98:2) to afford 2-aminoDMAP/
sulfonamides 7a−j (60−96% yield) as solid.
1
yield). Mp: 196−201 °C. H NMR (400 MHz, CDCl3) δ 1.08−1.26
(m, 2H), 1.26−1.36 (m, 1H), 1.37−1.51 (m, 1H), 1.69−1.86 (m, 3H),
2.24−2.13 (m, 1H), 2.41 (qd, J = 32, 9 Hz, 1H), 2.75 (s, 6H), 3.93 (d,
J = 9.4 Hz, 1H), 4.27 (qd, J = 10.9, 4.1 Hz, 1H), 5.38 (d, J = 2.1 Hz,
1H), 5.56 (dd, J = 6.1, 2.2 Hz, 1H), 7.41 (d, J = 6.1 Hz, 1H), 7.50 (dd,
J = 5.5, 3.0 Hz, 2H), 7.59 (dd, J = 5.5, 3.0 Hz, 2H). 13C NMR (100.6
MHz, CDCl3) δ 25.1, 25.6, 29.3, 34.0, 39.1, 52.2, 56.2, 88.0, 98.9,
122.8, 131.9, 133.4, 147.9, 155.7, 159.4, 168.9. HRMS (ESI) calcd for
C21H25N4O2 [M + H]+ 365.1978, found 365.1965.
Data for 7a. Colorless amorphous solid, 57 mg, 92% yield. Mp:
183−186 °C. [α]3D1 = +4.7 (c 0.25, CH2Cl2). H NMR (400 MHz,
1
CDCl3) δ 1.16−1.52 (m, 4H), 1.73 (m, 2H), 1.96−2.07 (m, 1H),
2.14−2.28 (m, 1H), 2.67 (s, 3H), 2.94 (s, 6H), 2.92−2.98 (m, 1H),
3.74−3.55 (m, 1H), 4.28 (d, J = 5.4 Hz, 1H), 5.59 (d, J = 2.2 Hz, 1H),
6.02 (dd, J = 2.3, 6.2 Hz, 1H), 7.72 (d, J 6.2 Hz, 1H); 1 exchangeable
sulfonamide H not located. 13C NMR (100.6 MHz, CDCl3) δ 24.4,
25.1, 33.4, 35.2, 39.2 (2C), 54.6, 62.2, 89.0, 100.2, 146.9, 156, 159.7.
IR (neat) 3376, 2921, 2854, 1608, 1530, 1495, 1444, 1259, 1016, 793.
HRMS (ESI) calcd for C14H25N4O2S [M + H]+ 313.1698, found
313.1688.
Preparation of 1 via Hydrazine-Mediated Cleavage of 14.
Compound 14 (94 mg, 0.25 mmol) was dissolved in 0.5 mL of
absolute ethanol, hydrazine hydrate (30 μL) was added, and the
mixture heated to reflux for 2 h. After cooling to rt, ethanol was
removed under high vacuum to afford a solid residue. The resulting
crude mixture was dissolved in 0.5 mL of dichloromethane and
subjected to flash column chromatography using dichloromethane
saturated with aqueous ammonia to afford the product 1 as a tan
brown solid (53 mg, 90% yield). (Identical analytical data were
obtained.)
Data for 7b. This reaction was carried out at −20 °C, and triflic
anhydride was added dropwise over 2 min. Amorphous off-white solid
44 mg, 60% yield. Mp: 230−235 °C. [α]3D1 = +14.1 (c 0.25, CH2Cl2).
1H NMR (400 MHz, d6-DMSO) δ 1.12−1.43 (m, 4H), 1.55−1.73 (m,
2H), 1.85−2.02 (m, 2H), 2.97 (s, 6H), 3.08−2.94 (m, 1H), 5.81 (d, J
= 2.3 Hz, 1H), 6.23 (dd, J = 2.4, 6.9 Hz, 1H), 6.72 (d, J = 5.9 Hz, 1H),
7.56 (d, J = 6.9 Hz, 1H). 13C NMR (100.6 MHz, d6-DMSO) δ 23.9,
24.3, 31.8, 34.4, 39.0, 57.4, 60.8, 88.0, 99.9, 116.1, 119.4, 122.6, 125.9,
139.6, 155.98, 156.17. IR (neat) 3342, 3111, 2926, 2849, 2458, 2108,
1651, 1724, 1523, 1372, 1204, 1173, 1142, 1085, 831, 792, 594. HRMS
(ESI) calcd for C14H22F3N4O2S [M + H]+ 367.1404, found 367.1416.
Data for 7c. Colorless amorphous solid, 73 mg, 94% yield. Mp:
Preparation of 2,4,6-Trimethyl-3-nitrobenzene-1-sulfonyl
Chloride. To the solid 2,4,6-trimethylbenzene-1-sulfonyl chloride
(437 mg, 2 mmol) was added 1 mL of fuming nitric acid dropwise in 1
min. The resulting brown solution was stirred 1 h at rt. It was then
diluted with 10 mL of ice-cold water; a yellow solid precipitation was
observed. This mixture was extracted with ether (25 mL) twice. The
obtained organic phase was dried over potassium carbonate and
filtered. The organic filtrate was concentrated under vacuum, and
product was recrystallized from n-pentane to give 2,4,6-trimethyl-3-
nitrobenzene-1-sulfonyl chloride as pale yellow needles (517 mg, 98%
176−178 °C. [α]3D1 = +85.7 (c 0.25, CH2Cl2). H NMR (400 MHz,
1
1
yield). Mp: 60−61 °C. H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H),
2.65 (s, 3H), 2.78 (s, 3H), 7.23 (s, 1H). 13C NMR (100.6 MHz,
CDCl3) δ 16.4, 17.6, 23.2, 131.0, 134.0, 135.9, 141.3, 152.3. IR (neat)
3648, 2987, 2884, 1594, 1525, 1442, 1372, 1363, 1177, 843, 671, 599.
HRMS (ESI) calcd for C9H11N2O4S [M − H]− 243.0440, found
243.0454. Due to ambiguity in HRMS analysis of the parent
compound, it was converted to the corresponding sulfonamide by
the following procedure: A 20 mL 1:1 DCM/ammonia (conc)
solution of 2,4,6-trimethyl-3-nitrobenzene-1-sulfonyl chloride (263
mg, 1 mmol) was vigorously stirred at rt for 2 h. The DCM phase was
dried over potassium carbonate, and the filtrate was concentrated
under vacuum. The corresponding sulfonamide product was
characterized by HRMS analysis without further purification.
CDCl3) δ 1.05−1.32 (m, 3H), 1.35−1.50 (m, 1H), 1.68 (m, 2H), 1.86
(m, 1H), 2.20−2.29 (m, 1H), 2.32 (s, 3H), 2.69 (dt, J = 4.2, 11.0 Hz,
1H), 2.92 (s, 6H), 3.51− 3.68 (m, 1H), 3.73 (d, J = 5.2 Hz, 1H), 5.19
(d, J = 2.1 Hz, 1H), 6.02 (dd, J = 2.2, 6.2 Hz, 1H), 7.02 (d, J = 8.0 Hz,
2H), 7.34 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 6.2 Hz, 1H); 1 exchangeable
sulfonamide H not located. 13C NMR (100.6 MHz, CDCl3) δ 19.9,
22.7, 23.4, 31.7, 33.2, 37.6, 52.1, 60.0, 87.8, 98.4, 125.2, 127.4, 136.4,
145.0, 154.2, 157.6. IR (neat) 3421, 3065, 2942, 2921, 2854, 1605,
1522, 1489, 1370, 1324, 1295, 1259, 1158, 1089, 799, 660, 567. HRMS
(ESI) calcd for C20H29N4O2S [M + H]+ 389.2011, found 389.2008.
Data for 7d. Colorless amorphous solid, 77 mg, 93% yield. Mp:
190−191 °C. [α]3D1 = +38.3 (c 0.25, CH2Cl2). H NMR (400 MHz,
1
CDCl3) δ 1.07−1.37 (m, 4H), 1.53−1.75 (m, 2H), 1.92−2.00 (m,
1H), 2.09 (m, 1H), 2.26 (s, 3H), 2.50 (s, 6H), 2.90 (s, 6H), 2.90−3.02
(m, 1H), 3.68 (m, 1H), 3.98 (d, J = 6.7 Hz, 1H), 5.41 (d, J = 2.2 Hz,
1H), 5.99 (dd, J = 2.2, 6.2 Hz, 1H), 6.85 (s, 2H), 7.68 (d, J = 6.2 Hz,
1H); 1 exchangeable sulfonamide H not located. 13C NMR (100.6
MHz, CDCl3) δ 20.9, 22.9, 24.4, 25.0, 33.5, 33.6, 39.2, 53.9, 60.3, 89.2,
100.1, 131.6, 135.7, 138.8, 141.1, 147.0, 155.9, 159.6. IR (neat) 3413,
3170, 2942, 2854, 1603, 1522, 1489, 1445, 1325, 1297, 1287, 1158,
1145, 1071, 800, 659. HRMS (ESI) calcd for C22H33N4O2S [M + H]+
417.2324, found 417.2325.
Preparation of 2,4,6-Triisopropyl-3-nitrobenzene-1-sulfonyl
Chloride. To the solid 2,4,6-triisopropylbenzene-1-sulfonyl chloride
(606 mg, 2 mmol) was added 2 mL of fuming nitric acid dropwise in 1
min. The resulting brown heterogeneous mixture was stirred for 5 h in
a water bath at 40 °C. It was then diluted with 20 mL of ice-cold water.
As a result, a yellow solid was precipitated out. This mixture was
extracted with ether (25 mL) twice. The obtained organic phase was
dried over potassium carbonate and filtered. The organic filtrate was
concentrated under vacuum. Product was chromatographed on a silica
gel column using 20:1 n-hexane/EtOAc to give 2,4,6-triisopropyl-3-
nitrobenzene-1-sulfonyl chloride as a pale yellow solid (626 mg, 90%
yield). Mp: 149−151 °C. 1H NMR (400 MHz, CDCl3) δ 1.20 (d, J =
6.8 Hz, 6H), 1.26 (d, J = 6.7 Hz, 6H), 1.30 (d, J = 7.1 Hz, 6H), 2.68
(sept, J = 6.8 Hz, 1H), 4.18 (sept, J = 6.8 Hz, 1H), 4.33 (bs, 1H), 7.42
(s, 1H). 13C NMR (100.6 MHz, CDCl3) δ 21.3, 23.6, 24.3, 29.6, 30.7,
125.6, 139.5, 141.5, 147.1, 150.0, 153.1. IR (neat) 2974, 2925, 2872,
Data for 7e. Colorless amorphous solid, 90 mg, 90% yield. Mp:
186−187 °C. [α]3D1 = +69.8 (c 0.25, CH2Cl2). H NMR (400 MHz,
1
CDCl3) δ 1.19 (d, J = 6.7 Hz, 6H), 1.24 (d, J = 7.0 Hz, 12H), 1.25−
1.36 (m, 4H), 1.59 (m, 1H), 1.69 (m, 1H), 1.94−2.10 (m, 2H), 2.89
(s, 6H), 2.83−2.93 (m, 1H), 3.19 (dt, J = 3.9, 10.4 Hz, 1H), 3.60−3.74
(m, 1H), 4.12 (sept, J = 7.2 Hz, 1H), 4.16 (sept, J = 6.4 Hz, 2H), 4.27
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Article
(d, J = 5.8 Hz, 1H), 5.56 (d, J = 2.2 Hz, 1H), 5.99 (dd, J = 2.2, 6.2 Hz,
1H), 7.10 (s, 2H), 7.66 (d, J = 6.2 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3) δ 23.6, 24.3, 24.8, 25.0, 29.6, 33.3, 33.4, 34.0, 39.2, 54.6, 59.6,
89.6, 100.1, 123.5, 135.0, 146.6, 149.9, 151.8, 155.9, 159.6. IR (neat)
3373, 2954, 2927, 2864, 1607, 1457, 1290, 1145. HRMS (ESI) calcd
for C28H45N4O2S [M + H]+ 501.3263, found 501.3273.
Data for 7f. Yellow amorphous solid, 88 mg, 96% yield. Mp: 181−
184 °C. [α]3D1 = +43.2 (c 0.25, CH2Cl2). 1H NMR (400 MHz, CDCl3)
δ 1.09−1.41 (m, 4H), 1.58−1.79 (m, 2H), 1.88−1.97 (m, 1H), 2.12−
2.20 (m, 1H), 2.23 (s, 3H), 2.30 (s, 3H), 2.59 (s, 3H), 2.86−2.96 (m,
1H), 2.93 (s, 6H), 3.54−3.77 (m, 1H), 3.91 (bs, 1H), 5.42 (d, J = 2.2
Hz, 1H), 6.01 (dd, J = 2.2, 6.2 Hz, 1H), 6.98 (s, 1H), 7.64 (d, J = 6.2
Hz, 1H); 1 exchangeable sulfonamide H not located. 13C NMR (100.6
MHz, CDCl3) δ 15.7, 17.1, 23.7, 24.4, 25.1, 33.5, 33.9, 39.2, 54.2,
61.40, 89.0, 100.4, 129.9, 131.4, 133.0, 138.1, 140.7, 146.5, 152.4,
155.9, 159.5. IR (neat) 3403, 3100, 2942, 2866, 1620, 1527, 1491,
1447, 1371, 1326, 1298, 1161, 1095, 842, 612. HRMS (ESI) calcd for
C22H32N5O4S [M + H]+ 462.2175, found 462.2159.
Data for 7g. Pale yellow fluffy solid, 104 mg, 96% yield. Mp: 150−
155 °C. [α]3D1 = +43.2 (c 0.25, CH2Cl2). 1H NMR (400 MHz, CDCl3)
δ 1.34−1.06 (m, 24H), 1.56 (d, J = 11.2 Hz, 1H), 1.66 (d, J = 10.0 Hz,
1H), 2.01−1.89 (m, 2H), 2.62 (sept, J = 6.8 Hz, 1H), 2.85 (s, 6H),
3.14 (dt, J = 3.9, 10.7 Hz, 1H), 3.48−3.66 (m, 1H), 3.92−4.18 (m,
2H), 4.21−4.41 (m, 1H), 5.48 (d, J = 2.1 Hz, 1H), 5.95 (dd, J = 2.3,
6.3 Hz, 1H), 7.26 (s, 1H), 7.56 (d, J = 6.2 Hz, 1H); 1 exchangeable
sulfonamide H not located. 13C NMR (100.6 MHz, CDCl3) δ 21.6,
21.7, 23.7, 24.1, 24.6, 24.8, 25.1, 28.9, 29.1, 30.5, 33.4, 33.6, 39.2, 55.1,
89.6, 100.5, 124.4, 138.5, 139.0, 143.2, 150.0, 152.4, 156.0. IR (neat)
3377, 2966, 2930, 2860, 1609, 1528, 1447, 1366, 1290, 1157, 1108.
HRMS (ESI) calcd for C28H44N5O4S [M + H]+ 546.3114, found
546.3107.
Data for 7h. White amorphous solid, 83 mg, 93% yield. Mp: 257−
258 °C. [α]3D1 = −4.6 (c 0.25, CH2Cl2). 1H NMR (400 MHz, CDCl3)
δ 0.61 (s, 3H), 0.93 (s, 3H), 1.53−1.22 (m, 5H), 1.83−1.59 (m, 3H),
1.88 (d, J = 18.4 Hz, 1H), 2.10−1.91 (m, 3H), 2.24−2.13 (m, 2H),
2.29 (dt, J = 3.6, 18.4 Hz, 1H), 2.56−2.38 (m, 1H), 2.90 (s, 6H), 3.13
(dt, J = 4.2, 10.5 Hz, 1H), 3.58 (d, J = 14.8 Hz, 1H), 3.73−3.85 (m,
1H), 4.21 (d, J = 6.3 Hz, 1H), 5.52 (d, J = 2.2 Hz, 1H), 6.01 (dd, J =
2.3, 6.2 Hz, 1H), 7.75 (d, J = 6.2 Hz, 1H), 7.83 (bs, 1H). 13C NMR
(100.6 MHz, CDCl3) δ 19.4, 19.9, 24.4, 24.8, 24.9, 27.0, 33.2, 35.2,
39.2, 42.5, 42.7, 47.8, 53.7, 58.3, 61.8, 88.9, 100.0, 147.2, 156.0, 159.6,
215.6. IR (neat) 3358, 2946, 2918, 2854, 1744, 1608, 1526, 1496,
1321, 1290, 1090, 807, 793. HRMS (ESI) calcd for C23H37N4O3S [M
+ H]+ 449.2586, found 449.2575.
Data for 7j. Off-white amorphous solid, 72 mg, 72% yield. Mp:
1
140−150 °C. [α]3D1 = +98.5 (c 0.25, CH2Cl2). H NMR (400 MHz,
CDCl3) δ 1.07 (s, 9H), 1.11−1.20 (m, 4H), 1.28 (s, 9H), 1.62 (t, J =
11.7 Hz, 2H), 1.80−1.88 (m, 1H), 2.20 (d, J = 13.2 Hz, 1H), 2.72 (td,
J = 11.0, 4.1 Hz, 1H), 2.83 (s, 6H), 3.39−3.50 (m, 1H), 3.71 (bs, 1H),
5.29 (d, J = 2.1 Hz, 1H), 5.95 (dd, J = 2.3, 6.3 Hz, 1H), 7.15 (d, J = 2.4
Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 6.3 Hz, 1H). Two
exchangeable protons not located. 13C NMR (100.6 MHz, CDCl3) δ
24.3, 25.0, 29.5, 31.2, 33.5, 34.0, 34.2, 35.4, 39.1, 55.1, 61.1, 89.4,
100.4, 122.2, 122.8, 128.7, 137.6, 141.1, 146.2, 152.1, 155.98, 156.17.
IR (neat) 3381, 3240, 2924, 2855, 1612, 1479, 1529, 1362, 1269, 1184,
1169, 1103, 698, 634, 598. HRMS (ESI) calcd for C27H43N4O3S [M +
H]+ 503.3056, found 503.3060.
General Procedure for Asymmetric Michael Addition of
Acetylacetone to trans-β-Nitrostyrenes. To a solution of trans-β-
nitrostyrene 8 or 11a−h (29.8 mg, 0.20 mmol) in toluene (1.0 mL)
were added 2-aminoDMAP/sulfonamide 7g (10.9 mg, 0.02 mmol)
and acetylacetone 9 (40 mg, 41 μL, 0.4 mmol). Upon consumption of
trans-β-nitrostyrene (monitored by TLC and p-anisaldehyde stain), the
reaction mixture was directly subjected to flash column chromatog-
raphy using EtOAc/n-hexanes as the eluant to afford the conjugate
addition products 10 and 12a−h as colorless solids.
(R)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione (10). Yield 44
mg, 89%. Analytical data matched previously reported value.25e HPLC
(AS-H, 85:15 n-hexane/isopropyl alcohol, 1 mL/min, 210 nm,): tmajor
= 37.2 min, tminor = 21.6 min, 93% ee; [α]3D1 = −75.5° (c 0.25, CH2Cl2).
(R)-3-(2-Nitro-1-(2-nitrophenyl)ethyl)pentane-2,4-dione
(12a). Yield 51 mg, 87%. Analytical data matched previously reported
value.25a HPLC (IA, 90:10 n-hexane/isopropyl alcohol, 1 mL/min, 210
nm): tmajor = 30.8 min, tminor = 34.3 min, 86% ee; [α]2D5 = −15.2 (c 0.25,
CHCl3).
(R)-3-(1-(2-Chlorophenyl)-2-nitroethyl)pentane-2,4-dione
(12b). Yield 52 mg, 91%. Analytical data matched previously reported
value.25c HPLC (IA, 90:10 n-hexane/isopropyl alcohol, 1 mL/min, 210
nm): tmajor = 18.0 min, tminor = 21.2 min, 75% ee; [α]2D5 = −158.92 (c
0.5, CHCl3).
(R)-3-(1-(3-Chlorophenyl)-2-nitroethyl)pentane-2,4-dione
(12c). Yield 50 mg, 88%. Analytical data matched previously reported
value.25c HPLC (IA, 90:10 n-hexane/isopropyl alcohol, 0.6 mL/min,
210 nm): tmajor = 22.2 min, tminor = 23.3 min, 97% ee; [α]2D5 = −45.92
(c 0.5, CHCl3).
(R)-3-(1-(4-Chlorophenyl)-2-nitroethyl)pentane-2,4-dione
(12d). Yield 53 mg, 93%. Analytical data matched previously reported
value.25c HPLC (IA, 90:10 n-hexane/isopropyl alcohol, 1 mL/min, 210
nm): tminor = 16.4 min, tmajor = 20.0 min, 99% ee; [α]2D5 = −16.24 (c 0.5,
CHCl3).
(S)-3-(2-Nitro-1-(thiophen-2-yl)ethyl)pentane-2,4-dione
(12e). Yield 39 mg, 76%. Analytical data matched previously reported
value.25c HPLC (AD-H, 85:15 n-hexane/isopropyl alcohol, 1 mL/min,
210 nm): tminor = 12.0 min, tmajor = 15.9 min, 85% ee; [α]2D5 = −87.62
(c 1.0, CHCl3).
Data for 7i. This compound was prepared by the following
procedure: Compound 2-aminoDMAP/sulfonamide 7h (90 mg, 0.2
mmol) was dissolved in ethanol (2.5 mL) and treated with NaBH4 (45
mg, 1.2 mmol) portionwise at 0 °C. The reaction mixture was warmed
to room temperature and stirred for 24 h. After this time, ethanol was
removed under reduced pressure, and the resulting residue was
dissolved in a saturated solution of NH4Cl (2 mL) and extracted twice
with CH2Cl2 (2 × 15 mL). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and then
concentrated. The residue was purified by flash chromatography on
silica gel using with EtOAc/TEA (98:2) as the eluant to afford 2-
aminoDMAP/Sulfonamide 7i as white amorphous solid (77 mg, 85%
(S)-3-(1-(Furan-2-yl)-2-nitroethyl)pentane-2,4-dione (12f).
Yield 44 mg, 91%. Analytical data matched previously reported
value.25a,c HPLC (AD-H, 85:15 n-hexane/isopropyl alcohol, 1 mL/
yield). Mp: 250−256 °C. [α]3D1 = −32.9 (c 0.25, CH2Cl2). H NMR
1
min, 210 nm): tmajor = 12.1 min, tminor = 16.1 min, 96% ee; [α]D25
−94.58° (c 1.0, CHCl3).
=
(400 MHz, CDCl3) δ 0.51 (s, 3H), 0.98 (s, 3H), 0.99−1.12 (m, 1H),
1.19−1.41 (m, 4H), 1.41−1.54 (m, 3H), 1.55−1.66 (m, 2H), 1.66−
1.83 (m, 4H), 1.99−2.09 (m, 2H), 2.16 (d, J = 12.4 Hz, 1H), 2.93 (s,
6H), 3.01(dt, J = 4.0, 11.2 Hz, 1H), 3.42 (d, J = 13.7 Hz, 1H), 3.71−
3.88 (m, 1H), 4.03 (dd, J = 4.3, 8.0 Hz, 1H), 4.10−4.25 (m, 1H), 5.53
(d, J = 2.2 Hz, 1H), 6.03 (dd, J = 6.2, 2.3 Hz, 1H), 7.74 (d, J = 6.2 Hz,
1H); 1 exchangeable sulfonamide H not located. 13C NMR (100.6
MHz, CDCl3) δ 20.0, 20.1, 24.5, 25.0, 27.3, 30.5, 33.4, 35.6, 38.8, 39.1,
44.3, 48.3, 50.2, 51.0, 53.7, 62.7, 76.4, 88.7, 100.2, 147.0, 156.1, 159.5.
IR (neat) 3381, 3307, 2955, 2924, 2856, 1614, 1530, 1507, 1447, 1311,
1299, 1263, 1173, 1136, 1079, 989, 807. HRMS (ESI) calcd for
C23H39N4O3S [M + H]+ 451.2743, found 451.2732.
(R)-3-(1-(4-(Benzyloxy)phenyl)-2-nitroethyl)pentane-2,4-
dione (12g). Yield 65 mg, 91%. Analytical data matched previously
reported value.25e HPLC (AD-H, 70:30 n-hexane/isopropyl alcohol, 1
mL/min, 210 nm): tminor = 11.1 min, tmajor = 14.7 min, 93% ee; [α]D25
−99.04 (c 0.25, CHCl3).
=
(R)-3-(1-(2-Methoxyphenyl)-2-nitroethyl)pentane-2,4-dione
(12h). Yield 52 mg, 90%. Analytical data matched previously reported
value.25c HPLC (IA, 98:2 n-hexane/isopropyl alcohol, 0.8 mL/min,
210 nm): tminor = 27.7 min, tmajor = 30.4 min, 90% ee; [α]2D5 = −195.12
(c 0.5, CHCl3).
1609
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Article
(h) Li, X.; Jiang, H.; Uffman, E. W.; Guo, L.; Zhang, Y.; Yang, X.;
Birman, V. B. J. Org. Chem. 2012, 77, 1722. (i) Birman, V. B.; Jiang, H.;
Li, X.; Guo, L.; Uffman, E. W. J. Am. Chem. Soc. 2006, 128, 6536.
(j) Yang, X.; Bumbu, V. D.; Birman, V. B. Org. Lett. 2011, 13, 4755.
(10) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional experimental details, copies of H and 13C NMR
spectra for all new compounds, and HPLC chromatograms of
Michael adducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
(11) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81, 785.
(12) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
(13) (a) Wutts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
AUTHOR INFORMATION
Corresponding Author
*E-mail: tanyeli@metu.edu.tr.
Organic Synthesis, 4th ed.; John Wiley & Sons Inc.: Hoboken, NJ,
■
́
2007. (b) Fuentes de Arriba, A. L.; Seisdedos, D. G.; Simon
́
, L.;
Alcazar, V.; Raposo, C.; Moran, J. R. J. Org. Chem. 2010, 75, 8303.
́
́
(c) Kim, Y. K.; Lee, S. J.; Ahn, K. H. J. Org. Chem. 2000, 65, 7807.
(d) Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41, 8431.
(14) Although Wulff (see ref 5) preferred the acronym “DMAP”,
here we find the word “2-aminoDMAP” more suitable since it is more
informative on the mode of action of the catalaphore (implication of
Brønsted basic nature due to its amidine structure; see also refs 8 and
9).
Present Address
†UNAM-Institute of Materials Science and Nanotechnology,
Bilkent University, 06800, Ankara, Turkey.
Notes
The authors declare no competing financial interest.
(15) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1995, 34, 1348. (b) Louie, J.; Hartwig, J. F. Tetrahedron Lett.
1995, 36, 3609.
(16) 2-HaloDMAPs 2a−c were prepared according to published
procedure. See: Cuperly, D.; Gros, P.; Fort, Y. J. Org. Chem. 2002, 67,
238.
ACKNOWLEDGMENTS
■
̈
̇
This work was supported by TUBITAK (110T870). M.I.
̈
̇
thanks TUBITAK for a graduate scholarship. The authors
̇
thank Irem Bakırcı, Nurdan Sargın, and Merve Kapucu for
HPLC measurements.
(17) See Supporting Information for a detailed discussion.
(18) Palladium-catalyzed selective mono-N-arylation of trans-cyclo-
hexane-1,2-diamine was shown to proceed well for aryl halides as
substrates. However, incompatability of 2-bromopyridine was
reported. See: (a) Frost, C. G.; Mendonca̧ , P. Tetrahedron: Asymmetry
1999, 10, 1831. See also: (b) Donati, D.; Ferrini, S.; Fusi, S.;
Ponticelli, F. Synthesis 2003, 2518.
(19) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727.
(20) For a palladium-catalyzed efficient synthesis of C2-symmetric
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