Regio-, Diastereo-, and Enantioselective Nitroso-Diels-Alder Reaction of 1,3-Diene-1-carbamates Catalyzed by Chiral Phosphoric Acids

Article abstract of DOI:10.1021/jacs.5b08515

Chiral phosphoric acid-catalyzed asymmetric nitroso-Diels-Alder reaction of nitrosoarenes with carbamate-dienes afforded cis-3,6-disubstituted dihydro-1,2-oxazines in high yields with excellent regio-, diastereo-, and enantioselectivities. Interestingly,

Full text of DOI:10.1021/jacs.5b08515

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Communication
Regio-, Diastereo-, and Enantioselective Nitroso Diels-Alder Reaction
of 1,3-Diene-1-carbamates, Catalyzed by Chiral Phosphoric acids
Jonathan Pous, Thibaut Courant, Guillaume Bernadat,
Bogdan I Iorga, Florent Blanchard, and Géraldine Masson
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Sep 2015
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Regio-, Diastereo- and Enantioselective Nitroso Diels-Alder
Reaction of 1,3-Diene-1-carbamates Catalyzed by Chiral
Phosphoric acids
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Jonathan Pous,† Thibaut Courant,† Guillaume Bernadat,‡ Bogdan I. Iorga,† Florent Blanchard,† and
Géraldine Masson*†
†Institut de Chimie des Substances Naturelles CNRS, Univ. ParisꢀSud, 1, Avenue de la Terrasse, 91198 Gifꢀsurꢀ
Yvette Cedex, France
‡ Équipe Molécules Fluorées et Chimie Médicinale, Laboratoire BioCIS (UMRꢀ8076) – LabEx LERMIT, Faculté
de Pharmacie, 5 Rue J.ꢀB. Clément, 92296 ChâtenayꢀMalabry Cedex, France
Supporting Information Placeholder
oselective NDA reactions were mainly restricted to speꢀ
cific nitroso dienophiles or cyclic dienes.
ABSTRACT: Chiral phosphoric acidꢀcatalyzed asymꢀ
metric nitrosoꢀDiels–Alder reaction of nitrosoarenes
with carbamateꢀdienes afforded cisꢀ3,6ꢀdisubstituted
dihydroꢀ1,2ꢀoxazines in high yields with excellent regioꢀ,
diastereoꢀ and enantioselectivities. Interestingly, we
observed that the catalyst is not only able to control enꢀ
antioselectivity but also is able to reverse regioselectivity
of the nonꢀcatalyzed nitrosoꢀDiels–Alder reaction. Regiꢀ
ochemistry reversal as well as asynchronous concerted
mechanism were confirmed by DFT calculations.
In light of the recent development of chiral phosphoric
acidꢀcatalyzed asymmetric transformations10 of secondꢀ
ary enamides11 that have been disclosed by us12 and othꢀ
ers, 13 we reasoned that 1,3ꢀdieneꢀ1ꢀcarbamates bearing
an NH directing group would be ideal partners for imꢀ
plementing an enantioselective catalytic NDA reaction.
Indeed, the dienecarbamate as well as nitrosoarene
could be activated through double hydrogen bonding to
control both regioꢀ and enantioselection (Scheme 1).
Scheme 1. Bifunctional catalyst for the enanti-
oselective NDA reaction
The nitroso Diels–Alder (NDA)1 reaction has attracted
considerable attention among synthetic chemists beꢀ
cause of the utility of the resulting 3,6ꢀdihydroꢀ1,2ꢀ
oxazines for the synthesis of natural products and bioꢀ
logically active molecules.1,2 Therefore, development of
asymmetric, catalytic versions of the NDA reaction have
been the subject of numerous researches.1 However,
control of the regioselectivity,3 fast background reacꢀ
tion(s) and the high propensity for dimerization of nitroꢀ
so compounds4 under acidic conditions made developꢀ
ment of a catalytic enantioselective intermolecular proꢀ
cess challenging.1,5 The first intermolecular enantioselecꢀ
tive NDA reaction was reported by Ukaji and Inomata
using a stoichiometric amount of a Zn(II) tartaric acid
To validate our hypothesis, we examined the reaction of
benzyl (pentaꢀ1,3ꢀdienꢀ1ꢀyl)carbamate 1a with commerꢀ
cially available nitrosobenzene 2a in the presence of 5
mol % of chiral phosphoric acid 4 in DCM at -30 °C (Taꢀ
ble 1). As shown in Table 1, all catalysts tested were caꢀ
pable of catalyzing the reaction with complete Oꢀ
regioselectivity3,8b,13f and excellent diastereoselectivity in
favor of the cisꢀdiastereomer. However, enantioselectiviꢀ
ty varied widely with the size of the substituents on the
3,3’ꢀpositions of 4 (entries 1ꢀ4).10 We found that the
ester complex.6
A major breakthrough came from
Yamamoto’s group,7 which reported that a copper comꢀ
plex could catalyze the intermolecular asymmetric NDA
reaction of 2ꢀnitrosopyridines with cyclic and acyclic
dienes. Although cycloadducts were generally isolated
with a high enantiomeric excess, this method is only
effective for 2ꢀnitrosopyridine dienophiles. Afterwards,
the same group8 described two efficient organocatalytic
asymmetric NDA reactions of cyclic dienes employing a
pyrrolidineꢀderived tetrazole8a,9 or BINOLꢀderived
Brønsted acid,8b respectively, as chiral catalyst. In spite
of these notable achievements, most of efficient enantiꢀ
bulkier
(S)ꢀ3,3'ꢀbis(2,4,6ꢀtriisopropylphenyl)ꢀBINOL
(TRIP) phosphoric acid 4d provided cycloadduct 3a in a
much higher yield and enantiomeric excess (entry 4).
When the catalyst loading was reduced to 1 mol%, the
enantioselectivity was maintained at almost the same
level, although the yield decreased to 33% (entry 5).
However, by simply increasing reaction time from 3 to 16
h, the yield of 3,6ꢀdihydroꢀ1,2ꢀoxazine 3a (entry 6) was
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enhanced to reach 98%. A survey of reaction solvents carbamates (Alloc, Fmoc, pꢀBrꢀCbz and perfluoroꢀCbz)
1
2
3
4
5
6
7
8
with 5 mol% of 4d revealed that toluene was effective to
slightly improve enantioselectivity (entry 7). Finally,
performing the reaction in toluene at a lower temperaꢀ
ture (ꢀ50°C) resulted in an improvement of both yield
and enantioselectivity (entry 8). It is interesting to note
that regioisomer 6a was not detected under phosphoric
acidꢀcatalyzed NDA reaction.
and amides affording highly substituted 3,6ꢀdihydroꢀ
1,2ꢀoxazines 3p-3u with excellent ee’s (Table 2). Absoꢀ
lute configuration of chiral centeres in compound 3u
was determined to be 3S and 6S by single crystal Xꢀray
diffraction analysis (see Supporting information).
Table 2. Substrate scope of 1,3-diene-1-
carbamates 1 and nitrosoarenes 2 with 1a.a-c
Table 1. Survey of reaction conditions for NDA
of 2a.a
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yield (%)b
(3a or
6a)
ee (%)c,d
(3a or
6a)
time
(h)
entry
cat
solvent
temp
1
2
3
4
5
6
7
8
9
a
4a
4b
4c
4d
4d
4d
4d
4d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
ꢀ30°C
ꢀ30°C
ꢀ30°C
ꢀ30°C
ꢀ30°C
ꢀ30°C
ꢀ30°C
ꢀ50°C
rt
3
3
60 (3a)
80 (3a)
47 (3a)
98 (3a)
33 (3a)
98 (3a)
73 (3a)
80 (3a)
80 (6a)d
20 (3a)
65 (3a)
17 (3a)
90 (3a)
87 (3a) e
88 (3a)
93 (3a)
98 (3a)
3
3
3
16
16
16
3
General conditions: 1a (0.05 mmol), 2a (0.10 mmol) and 4
(0.0025 mmol). b Yields refer to chromatographically pure product.
c Determined by HPLC analysis on chiral stationary phases. d >95:5
dr. e With 1 mol% of 4.
The scope of this Brønsted acidꢀcatalyzed NDA reacꢀ
tion was next investigated using our optimized condiꢀ
tions. As shown in table 2, various nitrosoarenes bearing
electronꢀdonating and withdrawing groups at the para
position14 could be successfully employed to afford 3,6ꢀ
dihydroꢀ1,2ꢀoxazines 3b-3i in good yields, with complete
regioselectivity and excellent diastereoꢀ and enantioseꢀ
lectivities. In addition, both ortho- and meta-substituted
nitrosoarenes efficiently provided the corresponding
cycloadducts 3j and 3k with excellent enantioselectiviꢀ
ties (Table 2). Pleasingly, this asymmetric NDA reaction
was found to be successful with various 1,3ꢀdiene partꢀ
ners (Table 2). Notably, several carbamateꢀdienes 1b-d
bearing alkyl (such as benzyl and hexyl) or aryl (such as
phenyl) groups at the Cꢀ4 position readily participated in
the reaction, leading to the obtention of 1,6ꢀdihydroꢀ1,2ꢀ
oxazines 3l-3n with yields and enantioselectivities of the
same order (Table 2). At the same time, the 3,4ꢀ
dialkylsubstituted diene 1e was also a successful subꢀ
strate of this NDA reaction, providing cycloadduct 3o
with an excellent enantioselectivity (91% ee). The presꢀ
ence of functional groups such as silyl ether (3p), alcohol
(3q) and double bond (3r) is well tolerated in the NDA
reaction as well. To our delight, the enantiomerically
pure dienecarbamate 1h having one endocyclic double
bond afforded 3r as a single diastereomer. Finally, the
catalytic system also proved to be efficient for various
a
General conditions: 1a (0.05 mmol), 2 (0.10 mmol) and 4
b
(0.0025 mmol) in toluene at ꢀ50°C.
graphically pure product. Determined by HPLC analysis on chiral
stationary phases. d Using catalyst 4e R = 2,4,6ꢀ(Me)3ꢀC6H2
Yields refer to chromatoꢀ
c
.
The following control experiments were carried out in
order to gain some mechanistic insight. When the reacꢀ
tion of 1,3ꢀdiene 1a and nitrosobenzene 2a was conductꢀ
ed in the absence of catalyst, the other regioisomer 6a
was exclusively obtained in 80% yield (entry 9, Table 1).
Moreover, as described in Table 1, only 1 mol% catalyst
was required to completely reverse the regioselectivity of
the NDA reaction (entry 6, Table 1).8,15 These findings
indicate that the chiral phosphoric acid catalyst is highly
active. To confirm this, we performed kinetic studies by
measuring the rate of conversion of 1a with or without
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Journal of the American Chemical Society
catalyst (see Supporting Information). As expected, we
found that the phosphoric acidꢀcatalyzed reaction was
1
2
3
4
5
6
7
8
much faster than the uncatalyzed one. To probe the
origin of the regioselectivity reversal,2b,3,5a,15 two different
transition state models, 7 and 8, were proposed (Scheme
2). The high azaphilicity of phosphoric acid catalysts9
could result in the preferential formation of Hꢀbond with
nitrogen N of nitroso 2, thus favoring the regioisomer 3.
In this assembly 8, the phosphoric acid would form hyꢀ
drogen bonds with 1,3ꢀdiene 1 and the nitrogen atom of
2 to favour the isomer 3.
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Scheme 2. Activation models and possible re-
action mechanism
R3
R2
NHCOR1
H
COR1
Figure 1. a) Free energy profiles for the spontaneous (uncatalyzed)
reactions yielding regioisomers 3x (blue) and 6x (red). b) Structure
of the transition state for the red pathway, with the lowest energy
barrier.
N
Slow
1 + 2
O
7
N
O
N
Ar
6
Ar
R3
4
R
R2
COR1
NHCOR1
Fast
R3
R2
R
N
H
(S)
O
R
Ar
Path a
1
N
P
O
O
O
O
N H
O
4
NHCOR1R3
(S)
8
Ar
R
R
3
R2
Ar
N
Fast
Path b
R
(S)
O
R3
9
R2
To improve our understanding of the mechanism and the
regioꢀ and stereochemistry observed experimentally,
DFT calculations were performed at the B3LYP/6ꢀ31G*
level.16 First, electronic structures of dienophile 2a and
Nꢀacylenamide (R1=Me, R2=Ph and R3=H) 1m were
calculated, and opposed to each other in order to locate
transition states leading to regioisomers 3x and 6x on
the potential energy surface (Figure 1). The free energy
difference between these two scenarios was consistent
with formation of 6 as the major product in the absence
of catalyst. Then, the equivalent transition states were
studied again, this time in the presence of each enantioꢀ
mer of phosphoric acid catalyst 4e (Figure 2), in order to
explain both the regioselectivity inversion and the stereꢀ
ochemical outcome of the reaction. Among the 4 possible
combinations of regio- and stereochemisty, the transiꢀ
tion state leading to regioꢀ and stereoisomer 3x in the
presence of (S)ꢀ4e catalyst had the lowest activation
energy (Figure 2). This result was in accordance with 3x
being indeed the major product obtained experimentally.
Calculation of the IRC of this theoretically most favored
pathway revealed an asynchronous concerted mechaꢀ
nism (Path a in Scheme 2)2b,5a,17 with a concomitant boatꢀ
toꢀhalfꢀchair conformational change of the dihydrooxaꢀ
zine ring, to the detriment of an alternative stepwise7
vinylogous Oꢀnitroso aldol reaction followed by intramoꢀ
lecular aminalization (Path b in Scheme 2; see also Supꢀ
porting information).
Figure 2. a) Free energy profiles for the (S) and (R)ꢀ4eꢀcatalyzed
reactions yielding enantiomers 3x (respectively red and blue). b)
Structure of the transition state for the red pathway, with the lowest
energy barrier.
To investigate and isolate the influence of this factor,
we performed a series of experiments involving non
phosphoric, nonꢀchiral acid catalysts with decreasing
pKa (see Supporting Information).10i The strongest acids
(CSA, pTSA) were found responsible of a total regioꢀ
chemistry inversion in favor of derivative 3,8b,13f to the
credit of our speculation, whereas reactions conducted in
the presence of weaker acids (such as benzoic acid)
yielded almost exclusively isomer 6. This hypothesis was
further studied in the course of a last series of computaꢀ
tional transition state searches, where the nitrogen atom
of the nitroso derivative was protonated in the absence of
any counteranion. The energy barriers found were in
agreement with the role supposedly played by the proton
in regioselectivity (see Supporting information).
Scheme 3. Synthetic transformation of 3,6-
dihydro-1,2-oxazines 3
NHCbz
NHPh
Et3SiH
BF3.OEt2
10% Pd/C,
H-Cube
Ph
Ph
N
O
N
O
OH
CH2Cl2, RT
77%
MeOH
95%
11
3a
10
Me
96% ee
Me
98% ee
Me
97% ee
The structure found for this transition state confirmed
dual activation of substrates by the catalyst, with the
formation of a hydrogen bond network. Moreover, on
this preferred pathway, we observed a total proton transꢀ
fer from phosphoric acid to the (basic) nitrogen belongꢀ
ing to the nitroso derivative. This finding led us to wonꢀ
der whether the sole protonation of the nitroso partner
sufficed to control the regioselectivity of the reaction.5a,15b
With optically pure 3,6ꢀdihydroꢀ1,2ꢀoxazines 3 obtained,
we next demonstrated the synthetic utility of the NDA
products (Scheme 3). Hydrogenation of the 1,2ꢀoxazine
product 4a using an HꢀCube apparatus (17) gave valuaꢀ
ble 1,4ꢀaminoꢀalcohol 10 in good yield after hydrogenolꢀ
ysis of the double bond, reduction of aminal and NꢀO
bond cleavage. Reduction of 4a with triethylsilane in the
presence of BF3.OEt2 gave direct access to the correꢀ
sponding 6ꢀmethylꢀ3,6ꢀdihydroꢀ1,2ꢀoxazine in 77% yield
without any loss of enantioselectivity (ee =96%).18
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A.; Whiting, A.; Wright, A. R. Adv. Synth. Catal. 2008, 350,
869.
(5) For the first asymmetric intramolecular NDA reaction,
see: (a) Chow, C. P.; Shea, K. J. J. Am. Chem. Soc. 2005, 127,
3678. See also: (b) Flower, K. R.; Lightfoot, A. P.; Wan, H.;
Whiting, A. J. Chem. Soc., Perkin Trans. 1 2002, 2058.
(6)Ding, X.; Ukaji, Y.; Fujinami, S.; Inomata, K. Chem. Lett.
2003, 32, 582.
In summary, we have developed an efficient enantioseꢀ
1
2
3
4
5
6
7
8
lective NDA reaction of nitrosoaryl derivatives with carꢀ
bamate dienes catalyzed by chiral phosphoric acids. This
cycloaddition is applicable to a wide range of nitrosoaryl
derivatives and carbamate dienes, providing a highly
diastereoꢀ and enantioselective route to (3S,6S)ꢀdihydroꢀ
1,2ꢀoxazines 3. Early mechanistic studies seem to indiꢀ
cate that the present NDA reaction proceeds via a highly
asynchronous concerted mechanism.
(7) (a) Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc.
2004, 126, 4128. (b) Yamamoto, Y.; Yamamoto, H. Angew.
Chem. Int. Ed. 2005, 44, 7082. Also, see: (c) Jana, C. K.;
Studer, A. Angew. Chem. Int. Ed. 2007, 46, 6542. (d) Jana, C.
K.; Grimme, S.; Studer, A. Chem. Eur. J. 2009, 15, 9078.
(8) (a) Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am.
Chem. Soc. 2004, 126, 5962. (b) Momiyama, N.; Yamamoto,
Y.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 1190.
(9) Sundén, H.; Dahlin, N.; Ibrahem, I.; Adolfsson, H.; Córꢀ
dova, A. Tetrahedron Lett. 2005, 46, 3385.
(10) For recent reviews on chiral phosphoric acid catalysis,
see: (a) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal.
2006, 348, 999. (b) Akiyama, T. Chem. Rev. 2007, 107, 5744.
(c) Terada, M. Chem. Commun. 2008, 4097. (d) Terada, M.
Synthesis 2010, 1929. (e) Terada, M. Bull. Chem. Soc. Jpn.
2010, 83, 101. (f) Kampen, D.; Reisinger, C. M.; List, B. Top.
Curr. Chem. 2010, 291, 395. (g) Rueping, M.; Kuenkel, A.;
Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539. (h) Parmar, D.;
Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047.
Also, see: (i) Akiyama, T.; Mori, K. Chem. Rev. 2015, 115, 9277.
(11) For reviews, see: (a) Matsubara, R.; Kobayashi, S. Acc.
Chem. Res. 2008, 41, 292. (b) Carbery, D. R. Org. Biomol.
Chem. 2008, 6, 3455. (c) Nugent, T. C.; ElꢀShazlya, M. Adv.
Synth. Catal. 2010, 352, 753. (d) Gopalaiah, K.; Kagan, H. B.
Chem. Rev. 2011, 111, 4599. (e) Bernadat, G.; Masson, G.
Synlett 2014, 25, 2842.
(12) (a) Lebée, C.; Kataja, A.; Blanchard, F.; Masson, G.
Chem. Eur. J. 2015, 21, 8399. (b) Dumoulin, A.; Lalli, C.;
Retailleau, P.; Masson, G. Chem. Commun. 2015, 51, 5383. (c)
Brioche, J.; Courant, T.; Alcaraz, L.; Stocks, M.; Furber, M.;
Zhu, J.; Masson, G. Adv. Synth. Catal. 2014, 356, 1719. (d)
Dagousset, G.; Erb, W.; Zhu, J.; Masson, G. Org. Lett. 2014, 16,
2554. (e) He, L; Laurent, G.; Retailleau, P.; Folléas, B.; Brayer,
J.ꢀL.; Masson, G. Angew. Chem. Int. Ed. 2013, 52,. (f) Alix, A.;
Lalli, C.; Retailleau, P.; Masson, G. J. Am. Chem. Soc. 2012,
134, 10389. (g) Dagousset, G.; Zhu, J.; Masson, G. J. Am.
Chem. Soc. 2011, 133, 14804.
(13) (a) Terada, M.; Machioka, K.; Sorimachi, K. Angew.
Chem. Int. Ed. 2006, 45, 2254. (b) Terada, M.; Machioka, K.;
Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 10336. (c) Terada,
M.; Machioka, K.; Sorimachi, K. Angew. Chem. Int. Ed. 2009,
48, 2553. (d) Terada, M.; Soga, K.; Momiyama, N. Angew.
Chem. Int. Ed. 2008, 47, 4122. (e) Guo, Q.ꢀX.; Peng, Y.ꢀG.;
Zhang, J.ꢀW.; Song, L.; Feng, Z.; Gong, L.ꢀZ. Org. Lett. 2009,
11, 4620. (f) Lu, M.; Lu, Y.; Zhu, D.; Zeng, X.; Li, X.; Zhong, G.
Angew. Chem. Int. Ed. 2010, 49, 8588.
9
ASSOCIATED CONTENT
Supporting Information
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Experimental procedures, characterization data, copies of
spectra, crystallographic data, and details of the DFT calcuꢀ
lations. This material is available free of charge on the ACS
Publication Website http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Dr. G. Masson : Institut de Chimie des Substances Natuꢀ
relles CNRS, Univ. ParisꢀSud, 1 Avenue de la Terrasse,
91198 Gifꢀ surꢀYvette Cedex, France
Fax: (+) 33 1 69077247
Eꢀmail: geraldine.masson@cnrs.fr
ACKNOWLEDGMENT
We thank ICSN for financial support and doctoral fellowꢀ
ships to J.P.; T.C. thanks MESR for a doctoral fellowship,
University of Paris XI. The IT department of Université
ParisꢀSud as well as ICSN are acknowledged for providing
computing resources.
REFERENCES
(1) For review of NDA reactions, see: (a) Waldmann, H. Syn-
thesis 1994, 535. (b) Streith, J.; Defoin, A. Synthesis 1994,
1107. (c) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317.
(d) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005,
3514. (e) Yamamoto, Y.; Yamamoto, H. Eur. J. Org. Chem.
2006, 2031. (f) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc.
Jpn. 2007, 80, 595.
(2) For review on the synthetic applications of NDA products
see: (a) Bodnar, B. S.; Miller, M. J. Angew. Chem. Int. Ed.
2011, 50, 5630. (b) EschenbrennerꢀLux, V.; Kumar, K.;
Waldmann, H. Angew. Chem. Int. Ed. 2014, 53, 11146. (c)
Carosso, S.; Miller, M. J. Org. Biomol. Chem. 2014, 12, 7445.
For selected examples, see: (d) Belleau, B.; AuꢀYoung, Y. K. J.
Am. Chem. Soc. 1963, 85, 64. (e) Calvet, G.; Dussaussois, M.;
Blanchard N.; Kouklovsky, C. Org. Lett. 2004, 6, 2449. (f) Li,
F.; Yang, B.; Miller, M. J.; Zajicek, J.; Noll, B. C.; Möllmann,
U.; Dahseand, H.ꢀM.; Miller, P. A. Org. Lett. 2007, 9, 2923..
(g) Krchňák, V.; Zajíček, J.; Miller, P. A.; Miller, M. J. J. Org.
Chem. 2011, 76, 10249.
(3) For discussions on regioselectivity in NDA reaction, see:
(a) Sauer, J.; Sustmann, R. Angew. Chem. Int. Ed. 1980, 19,
779. (b) Boger, D. L.; Patel, M.; Takusagawa, F. J. Org. Chem.
1985, 50, 1911. (c) Defoin, A.; Fritz; Schmidlin, C.; Streith J.
Helv. Chim. Acta 1987, 70, 554. (d) Leach, A. G.; Houk, K. N. J.
Org. Chem. 2001, 66, 5192. (e) Galvani, G.; Lett, R.;
Kouklovsky, C. Chem. Eur. J. 2013, 19, 15604. Also, see: (f)
Janey, J. M. Angew. Chem. Int. Ed. 2005, 44, 4292.
(4) (a) Banks, R. E.; Barlow, M. G.; Haszeldine, R. N. J.
Chem. Soc. 1965, 4714. (b) Lightfoot, A. P.; Pritchard, R. G.;
Wan, H.; Warren, J. E., Whiting A. Chem. Commun. 2002,
2072. (c) Quek, S. K.; Lyapkalo, I. M.; Huynh, H. V. Synthesis
2006, 1423. (d) Howard, J. A. K.; Ilyashenko, G.; Sparkes, H.
(14) Molander, G. A.; Cavalcanti, L. N. J. Org. Chem. 2012,
77, 4402.
(15) Example of reverse regioselectivity, see (a) Momiyama,
N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5360. (b)
Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127,
1080. (c) Guo, H. M.; Cheng, L.; Cun, L. F.; Gong, L. Z.; Mi, A.
Q.; Jiang, Y. Z. Chem. Commun. 2006, 429.
(16) (a) Kohn, W.; Sham, L. J. Phys. Rev. 1965, 140, A1133.
(b) Hohenberg, P.; Kohn, W. Phys. Rev. 1964, 136, B864. (c)
Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A., Ab
Initio Molecular Orbital Theory; Wiley: New York, 1986.
(17) (a) Leach, A. G.; Houk, K. N. Chem. Commun. 2002,
1243. (b) Tran, A. T.; Liu, P.; Houk, K. N.; Nicholas K. M. J.
Org. Chem. 2014, 79, 5617.
(18) Kumarn, S.; Shaw, D. M.; Longbottom, D. A.; Ley, S. V.
Org. Lett. 2005, 7, 4189.
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