Efficient synthesis of imino-methano Troeger bases by nitrene insertions into C-N bonds

Article abstract of DOI:10.1021/ol4016892

A direct nitrene insertion into C-N bonds is observed upon treatment of methano-Troeger bases with arylsulfonyl iminophenyliodinanes under copper and dirhodium catalysis. Novel cyclic imino-methano Troeger bases are obtained (55-88%). Enantiopure products (ee ≥ 99%) can be obtained with tailored substrates.

Full text of DOI:10.1021/ol4016892

ORGANIC
LETTERS
2013
Vol. 15, No. 15
3930–3933
Efficient Synthesis of Imino-methano
€
Troger Bases by Nitrene Insertions
into CꢀN Bonds
†
Sandip A. Pujari, Laure Guenee, and Jerome Lacour*
‡
,†
ꢀ ꢀ
ꢀ ^
University of Geneva, Department of Organic Chemistry, 30 Quai Ernest Ansermet,
CH-1211 Geneva 4, Switzerland, and Laboratory of Crystallography,
ꢁ
University of Geneva, quai Ernest Ansermet 24, CH-1211 Geneve 4, Switzerland
Jerome.Lacour@unige.ch
Received June 14, 2013
ABSTRACT
€
A direct nitrene insertion into CꢀN bonds is observed upon treatment of methano-Troger bases with arylsulfonyl iminophenyliodinanes under
€
copper and dirhodium catalysis. Novel cyclic imino-methano Troger bases are obtained (55ꢀ88%). Enantiopure products (ee g 99%) can be
obtained with tailored substrates.
The metal catalyzed decomposition of arylsulfonyl imi-
nophenyliodinanes is a powerful method to generate metal
nitrenes. These intermediates are frequently used to pro-
Scheme 1. Reactivity with Arylsulfonyl Iminophenyliodinanes
mote aziridinations and CꢀH aminations (insertions).1
When reacted with tertiary sp3 and sp2 nitrogen atoms,
they afford NþꢀNꢀ ylides (aminimides) as products.2
Usually, sulfonyl aminimides are inert compounds decom-
posing only at a very high temperature.2,3 Herein, in sharp
contrast, we report that metal nitrenes derived from
† Department of Organic Chemistry.
‡ Laboratory of Crystallography.
€
arylsulfonyl iminophenyliodinanes react with methano-Troger
(1) (a) Dequirez, G.; Pons, V.; Dauban, P. Angew. Chem., Int. Ed.
2012, 51, 7384–7395. (b) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Acc.
Chem. Res. 2012, 45, 911–922. (c) Collet, F.; Lescot, C.; Dauban, P.
Chem. Soc. Rev. 2011, 40, 1926–1936. (d) Lebel, H. In Catalyzed Carbon-
Heteroatom Bond Formation; Yudin, A. K., Ed.; Wiley-VCH: Weinheim,
Germany, 2011; pp 137ꢀ155. (e) Driver, T. G. Org. Biomol. Chem. 2010,
8, 3831–3846. (f) Feast, G. C.; Page, L. W.; Robertson, J. Chem.
Commun. 2010, 46, 2835–2837. (g) Fantauzzi, S.; Caselli, A.; Gallo, E.
Dalton Trans. 2009, 5434–5443. (h) Davies, H. M. L.; Manning, J. R.
Nature 2008, 451, 417–424. (i) Diaz-Requejo, M. M.; Perez, P. J. Chem.
Rev. 2008, 108, 3379–3394. (j) Halfen, J. A. Curr. Org. Chem. 2005, 9,
bases 14 to form highly reactive aminimides that undergo facile
CꢀN insertion reactions (Scheme 1). Novel imino-methano
€
Troger bases 2 are afforded in good yields (55ꢀ88%) under
mild reaction conditions (20ꢀ40 °C). Both copper and rho-
dium catalysts mediate the reaction, and enantiopure products
(ee g 99%) can be obtained with tailored substrates.
Recently, it was shown that compounds 1, interesting
chiralmolecules duetothe presenceofstereogenicnitrogen
€
657–669. (k) Muller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905–2919.
(2) McKillip, W. J.; Sedor, E. A.; Culberts, B. M.; Wawzonek, S.
Chem. Rev. 1973, 73, 255–281.
(3) (a) Li, J.; Cisar, J. S.; Zhou, C.-Y.; Vera, B.; Williams, H.;
€
(4) (a) Troger, J. J. Prakt. Chem. 1887, 36, 225–245. (b) Runarsson,
O. V.; Artacho, J.; Warnmark, K. Eur. J. Org. Chem. 2012, 7015–7041.
(c) Sergeyev, S. Helv. Chim. Acta 2009, 92, 415–444. (d) Dolensky, B.;
Elguero, J.; Kral, V.; Pardo, C.; Valik, M. Adv. Heterocycl. Chem. 2007,
93, 1–56. (e) Demeunynck, M.; Tatibouet, A. Prog. Heterocycl. Chem.
1999, 11, 1–20.
Rodrıguez, A. D.; Cravatt, B. F.; Romo, D. Nature Chem. 2013, 5,
´
510–517. (b) Trost, B. M.; O’Boyle, B. M.; Torres, W.; Ameriks, M. K.
Chem.;Eur. J. 2011, 17, 7890–7903. (c) Jain, S. L.; Sharma, V. B.; Sain,
B. Tetrahedron Lett. 2003, 44, 4385–4387.
r
10.1021/ol4016892
Published on Web 07/15/2013
2013 American Chemical Society

atoms, react with metal carbenes to afford configuration-
€
probably, these products result from the formation of
NþꢀCꢀ ylide intermediates that undergo a Stevens-like
rearrangement.6 Considering the analogy between car-
benes and nitrenes,7 focus was directed toward studying
5
ally stable ethano-Troger bases in a single step. Most
Table 2. Substrate Scopea
€
the reactivity of Troger bases 1 with arylsulfonyl
iminophenyliodinanes.8
entry
R
substrate
methodb
time
yield (%)c
1
2
3
4
5
6
OMe
CO2Et
I
1b
1c
1d
1b
1c
1d
A
A
A
B
B
B
6 h
84
77
61
72
69
56
24 h
24 h
6 h
Table 1. Optimization of Reaction Conditionsa
OMe
CO2Et
I
16 h
8 h
Troger base (1 equiv), PhINTs (2 equiv), 20 °C. b Method A:
Rh2(esp)2 (2 mol %), CH2Cl2 (0.05 M). Method B: Cu(OTf)2 (10 mol %),
CH3CN (0.05 M). c Isolated yields.
a
€
entry
catalyst
mol %
solvent
time
yield (%)b
1
2
3
4
5
6
7
8
9
Cu(OTf)2
CuTC
5
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
toluene
CH2Cl2
16 h
16 h
16 h
1 h
67
48
CuI
5
24
Table 3. In Situ Generation of Sulfonyl Iminophenyliodinanesa
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Rh2(esp)2
Rh2(OAc)4
Rh2(OAc)4
5
81
10
10
2
1 h
88
30 h
4 h
36
76
2
24 h
24 h
(12)c
(40)c
2
a 1a (1 equiv), copper salt or Rh(II) complex, PhINTs (2 equiv),
solvent (0.05 M), 20 °C. b Isolated yields. c Conversion (%) by NMR.
Compound 1a (Scheme 1, R = Me) was treated with
PhINTs9 in the presence of copper salts and rhodium(II)
complexes. To our satisfaction, the reaction proceeded
at ambient temperature in the presence of 5 mol % of
Cu(OTf)2, CuTC, or CuI to afford the insertion product
(Table 1, entries 1 to3). The structure of 2a was determined
by NMR spectroscopy and confirmed by X-ray crystal-
lographic analysis (see Supporting Information).10 Better
yields were obtained with Cu(OTf)2 over CuTC and CuI
ꢀ ꢀ
(5) (a) Sharma, A.; Guenee, L.; Naubron, J.-V.; Lacour, J. Angew.
Chem., Int. Ed. 2011, 50, 3677–3680. (b) Sharma, A.; Besnard, C.;
ꢀ ꢀ
Guenee, L.; Lacour, J. Org. Biomol. Chem. 2012, 10, 966–969.
(6) (a) Vanecko, J. A.; Wan, H.; West, F. G. Tetrahedron 2006, 62,
1043–1062. (b) Kumar, R. R.; Vanitha, K. A.; Perumal, S. Stevens
rearrangement. Name Reactions for Homologations, Pt. 2; John Wiley &
Sons, Inc.: 2009; pp 516ꢀ530. (c) Sweeney, J. Chem. Soc. Rev. 2009, 38,
1027–1038. (d) Bach, R.; Harthong, S.; Lacour, J. Nitrogen- and sulfur-
based Stevens and related rearrangements. In Comprehensive Organic
Synthesis, 2nd ed.; Molander, G., Knochel, P., Eds.; Elsevier: London, 2014
in press.
(7) (a) Wentrup, C. Acc. Chem. Res. 2011, 44, 393–404. (b) Doyle,
M. P. Synthetic Carbene and Nitrene Chemistry. In Reactive Intermedi-
ate Chemistry; Moss, R. A., Platz, M., Jones, M., Eds.; Wiley-Interscience:
Hoboken, NJ, 2004; pp 561ꢀ592.
a Isolated yields.
(67% vs 48% and 24% respectively). With Cu(OTf)2 as the
catalyst, improved yields were obtained using a shorter
reaction time (1 h vs 16 h), increased catalyst loading
(10 mol % vs 5 mol %), and acetonitrile instead of CH2Cl2
as the solvent (Table 1, entries 4 to 6).11 With dirhodium
(8) Aminimides other than sulfonyl derivatives can react in Stevens-
like rearrangements. These reactions are known as Wawzonek rearran-
gements: Wawzonek, S.; Yeakey, E. J. Am. Chem. Soc. 1960, 82, 5718–
5721.
(9) (a) Abramovitch, R. A.; Bailey, T. D.; Takaya, T.; Uma, V.
J. Org. Chem. 1974, 39, 340–345. (b) Yamada, Y.; Yamamoto, T.;
Okawara, M. Chem. Lett. 1975, 361–362.
(10) CCDC 942112ꢀ942114 contains the supplementary crystallo-
graphic data for this paper (2a, 7, and 10a). These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(11) Most probably, the increase in reactivity with acetonitrile as
solvent over CH2Cl2 is due to an improved solubility of the catalytic
species.
Org. Lett., Vol. 15, No. 15, 2013
3931

a
€
Table 4. Reactivity of Bis-ortho Substituted Troger Bases
Scheme 2. Deprotection of the Nosyl Group
Scheme 3. Mechanistic Rationalea
a Preferred regioselectivity with X = NO2 and Y = OMe (substrate 6
and product 7).
catalysts, as expected the Rh2(esp)212 complex performed
quite better (76% yield, Table 1, entry 7) than Rh2(OAc)4.
In the latter case, only partial conversion of starting
material 1a was observed even after a prolonged reaction
time (Table 1, entries 8 and 9). It is also worth noting that
the above reactions exhibited excellent chemoselectivity
since, despite the presence of reactive benzylic positions,
products of CꢀH insertion (amination) reactions are not
observed.13
With optimized conditions in hand (Table 1, entry 5 or 7),
€
a
Troger base 8 (1 equiv), PhINTs (3 equiv). b Method A: Rh2(esp)2
€
(2 mol %), CH2Cl2. c Method B: Cu(OTf)2 (10 mol %), CH3CN.
electron-rich and -poor substrates were studied. Troger
bases carrying methoxy, ethyl ester, and iodo substituents
were prepared (1b to 1d, R = OMe, CO2Et and I, Scheme 1,
Table 2).14 The reactions proceeded in all instances. Better
yields were obtained under Rh2(esp)2 catalysis (method A,
61ꢀ84% yields) over Cu(OTf)2 (method B, 56ꢀ72%
yields). Reactions were faster with electron-rich 1b (R =
OMe, Table 2, entries 1 and 4) over electron-poor substrates
1c and 1d. With 2d, a certain sensitivity to the purification
conditions was noticed explaining probably the lower
yields.15
Care was taken to also perform the reaction under
conditions permitting the in situ formation of the metal
nitrene intermediates directly from sulfonamides.16 To our
satisfaction, product 2a was formed in 67% yield (Table 3,
entry 1). In thiscase and in the following reactions of Table3,
it was necessary to warm the medium to 40 °C and extend
the reaction time to 16 or even 48 h. Substrates 1a and 1b
reacted well with p-nitrobenzenesulfonamide to afford pro-
ducts 2e and 2f in 79% and 74% yields respectively (Table 3,
(12) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem.
Soc. 2004, 126, 15378–15379.
(13) Amination reactions occur only on hindered substrates such as
€
bis-ortho substituted Troger bases. See Table 4.
(14) (a) Jensen, J.; Warnmark, K. Synthesis 2001, 1873–1877.
(b) Goswami, S.; Ghosh, K.; Dasgupta, S. J. Org. Chem. 2000, 65,
1907–1914. (c) Miller, T. R.; Wagner, E. C. J. Am. Chem. Soc. 1941, 63,
832–836.
(16) (a) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40,
598–600. (b) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am.
ꢁ
(15) In this particular case, flash chromatography must be conducted
with neutral alumina instead of silica gel.
Chem. Soc. 2001, 123, 6935–6936. (c) Dauban, P.; Saniere, L.; Tarrade,
A.; Dodd, R. H. J. Am. Chem. Soc. 2001, 123, 7707–7708.
3932
Org. Lett., Vol. 15, No. 15, 2013

entries 2 and 3). Only in the case of electron-withdrawing
substrate 1c, product 2g was afforded in moderate yield
(55%, Table 3, entry 4). With 2e, it was possible to remove
the p-nosyl group by treatment with thiophenol/K2CO3 and
afford the unprotected hydrazine 3 (Scheme 2, 75% yield).17
The reaction was then performed with enantiopure
(þ)-1a. Unfortunately, product 2a was isolated in racemic
form using optimized conditions for Cu(II) and Rh(II)
catalysts and variants performed at lower temperatures.
To understand the origin of the racemization, 2a was
separated into single enantiomers using a CSP-HPLC
resolution protocol (see the Supporting Information).
The compound was found to be configurationally stable
in neutral media. However, by subjecting one of the
enantiomers to the reaction conditions for 4 h, a decrease
of the enantiomeric excess of 2a from 99% to 50% in the
case of Rh2(esp)2 and a complete racemization in the pre-
sence of Cu(OTf)2 were observed. This indicates that the
racemization can occur notonlyduringthe formation of2a
but also after the product has been formed.
planarization of the core. Intermediates 5 can be formed
either directly from 4 or from products 2 through a ring
opening induced by the Lewis acid metal catalysts.19
This proposal also explains the lower reactivity of
electron-poor bridgehead nitrogen atoms (e.g., in 1c and
1d) which was further confirmed by an experiment using
€
unsymmetrically substituted Troger base 6 (Scheme 3:
X = NO2, Y = OMe) carrying both electron-donating and
-withdrawing substituents on the two aromatic rings.20
A
single regioisomer was obtained (7, 45%). It results clearly
from an initial attack on the electron-rich nitrogen atom (para
to the methoxy group), the structure being ascertained by
X-ray crystallographic analysis (Supporting Information).21
Finally, to address the lack of configurational stability
of rearranged products 2, the introduction of substituents
ortho to the nitrogen atoms was pursued (Table 4).22
Treatment of 8a (R1 = Me, R2 = H, R3 = Me) with
PhINTs and Rh2(esp)2 afforded desired product 9a in 24%
yield along with novel CꢀH amination product 10a (22%)
as a single diastereomer (Table 4, entry 1). The reaction
required 3 equiv of PhINTs and a longer duration for
completion. Similar results were obtained with Cu(OTf)2
(Table 4, entry 2). The structure of 10a was confirmed by
X-ray analysis. Clearly, in this present case, the hindrance
around the nitrogen atoms23 favors an alternative amina-
tion on the benzylic position. A similar reactivity was
observedwith8band 8ccarryingortho-methyl substituents
(Table 4, entries 3 and 4).24 A stronger inclination toward
the CꢀH insertion reaction was noticed in the presence of
bromine atoms at meta and ortho positions (Table 4,
entries 4 and 5). Substrate 8a was then resolved into single
enantiomers.25 Satisfyingly, under Cu(OTf)2 catalysis, the
reaction of (ꢀ)-8a yielded rearranged product (ꢀ)-9a with
a complete transfer of chirality (8a g 99% ee).26 In the
presenceofRh2(esp)2, using(þ)-8a asthe substrate, (þ)-9a
was obtained in 92% ee along with racemic 10a.
The racemization and the insertion reactivity as a whole
can be rationalized in terms of mechanism (Scheme 3).
It involves the catalytic generation of electrophilic metal
€
nitrenes and additions of Troger bases 1 to these inter-
mediates. Sulfonyl aminimide moieties of type 4 result.
€
Then, by a CꢀN bond cleavagethatistraditionalinTroger
base chemistry upon quaternization of one of the nitrogen
atoms,18 zwitterionic ring-opened species of type 5 are
formed that collapse subsequently to form the imino-
€
methano Troger bases 2. Under this hypothesis, the ob-
served loss of enantiomeric purity results probably
from the formation of monocyclic intermediates 5 which
have the possibility to racemize through a complete
(17) (a) Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373–6374. (b) Mao, H.; Joly, G. J.; Peeters, K.; Hoornaert,
G. J.; Compernolle, F. Tetrahedron 2001, 57, 6955–6967.
€
(18) Trapp, O.; Trapp, G.; Kong, J. W.; Hahn, U.; Vogtle, F.;
Schurig, V. Chem.;Eur. J. 2002, 8, 3629–3634.
€
In conclusion, methano-Troger bases 1 react with aryl-
sulfonyl iminophenyliodinanes (Cu(II) or Rh(II) catalysis,
€
(19) The Troger base catalyzed aziridination of chalcones with
€
20 to 40 °C) to form imino-methano Troger bases 2 in
O-mesitylenesulfonylhydroxylamine as reagent has been reported
(Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y. Angew. Chem., Int. Ed.
2006, 45, 8005–8008). Under these conditions, an aminimide intermedi-
ate could formally form. However, if it is the case, it does not undergo the
subsequent rearrangement observed herein.
(20) Pardo, C.; Ramos, M.; Fruchier, A.; Elguero, J. Magn. Reson.
Chem. 1996, 34, 708–710.
good yields (55ꢀ88%). Sulfonyl aminimides are probably
formed that insert in adjacent CꢀN bonds via a two-step
€
mechanism. While classic enantiopure Troger bases afford
racemic products, bis-ortho substituted derivatives can
react with a full transfer of chirality (ee g 99%).
(21) Interestingly, this reaction contradicts the regioselectivity ob-
served in the reaction of 6 with R-diazo diester reagents under Rh(II)-
catalysis at elevated temperatures (ref 5a). It suggests that the first step of
these nitrene-mediated reactions is strictly under kinetic rather than
thermodynamic control.
Acknowledgment. We thank the University of Geneva,
the Swiss National Science Foundation, the NCCR Chem-
ical Biology for financial support. We acknowledge the
contributions of the Sciences Mass Spectrometry (SMS)
platform at the Faculty of Sciences, University of Geneva.
(22) It has been established that compounds of type 8 (R3 = Me or Br),
€
unlike Troger bases 1, are highly stable as single enantiomers, even in
strongly acidic media: Lenev, D. A.; Lyssenko, K. A.; Golovanov, D. G.;
Buss, V.; Kostyanovsky, R. G. Chem.;Eur. J. 2006, 12, 6412–6418.
(23) (a) Gao, X.; Hampton, C. S.; Harmata, M. Eur. J. Org. Chem.
2012, 7053–7056. (b) Pereira, R.; Cvengros, J. J. Organomet. Chem.
2013, 729, 81–85.
(24) All products 10 are afforded as single diastereomers. The
proposed configuration is based on the X-ray diffraction analysis of
10a (see Supporting Information).
(25) Didier, D.; Tylleman, B.; Lambert, N.; Velde, C.; Blockhuys, F.;
Collas, A.; Sergeyev, S. Tetrahedron 2008, 64, 6252–6262.
(26) Insertion product 10a is again obtained as a single diastereomer
but only in 19% ee.
Supporting Information Available. Synthesis and spec-
€
tral caracterization imino-methano Troger bases 2. CSP-
HPLC determination of the enantiomeric purity of 9a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 15, 2013
3933