Functionally diverse nucleophilic trapping of iminium intermediates generated utilizing visible light

Article abstract of DOI:10.1021/ol202883v

Our previous studies into visible-light-mediated aza-Henry reactions demonstrated that molecular oxygen played a vital role in catalyst turnover as well as the production of base to facilitate the nucleophilic addition of nitroalkanes. Herein, improved conditions for the generation of iminium ions from tetrahydroisoquinolines that allow for versatile nucleophilic trapping are reported. The new conditions provide access to a diverse range of functionality under mild, anaerobic reaction conditions as well as mechanistic insights into the photoredox cycle.

Full text of DOI:10.1021/ol202883v

ORGANIC
LETTERS
2012
Vol. 14, No. 1
94–97
Functionally Diverse Nucleophilic
Trapping of Iminium Intermediates
Generated Utilizing Visible Light
David B. Freeman, Laura Furst, Allison G. Condie, and Corey R. J. Stephenson*
Department of Chemistry, Boston University, Boston, Massachusetts 02215,
United States
crjsteph@bu.edu
Received October 25, 2011
ABSTRACT
Our previous studies into visible-light-mediated aza-Henry reactions demonstrated that molecular oxygen played a vital role in catalyst turnover
as well as the production of base to facilitate the nucleophilic addition of nitroalkanes. Herein, improved conditions for the generation of iminium
ions from tetrahydroisoquinolines that allow for versatile nucleophilic trapping are reported. The new conditions provide access to a diverse
range of functionality under mild, anaerobic reaction conditions as well as mechanistic insights into the photoredox cycle.
The catalytic oxidation of R-amino CꢀH bonds to
generate reactive intermediates, specifically iminium ions,
is a useful method in organic synthesis.1 Exploitation of
these reactive intermediates via reaction with diverse nu-
cleophiles can lead to biologically relevant structural mo-
tifs including β-amino acids and potential drug candidates
such as noscapine.2 The pioneering work of Li3 and
Murahashi4 has demonstrated the utility of metal catalysis
to access such functionally distinct architectures via R-amino
CꢀH activation.5,6 Herein we report the advancement of
R-amino CꢀH functionalization via visible-light-mediated
photoredox catalysis.
Free-radical chemistry has played a crucial role in
accessing complex molecular frameworks through chemo-
selective transformations including polyene cyclization
cascades and reduction/oxidation of remote unsaturated
carbons.7 Recent efforts emphasizing benign, mild cataly-
tic systems,8 including copper catalysis3 and visible-light-
mediated organic reactions,9 represent appealing alter-
natives.10,11 Visible-light-mediated photoredox catalysis
using substoichiometric quantities (typically 1 mol %)
of metal complexes to facilitate redox cycles using mild
(1) For reviews on cross dehydrogenative coupling, see: (a) Yeung,
C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (b) Li, C.-J. Acc. Chem.
Res. 2010, 43, 581. (c) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (c)
Murahashi, S.-I.; Zhang, D. Chem. Soc. Rev. 2008, 37, 1490.
(2) (a) Soriano, M. D. P. C; Shankaraiah, N.; Santos, L. S. Tetra-
hedron Lett. 2010, 51, 1770. (b) Mahmoudian, L. S.; Rahimi-Moghad-
dam, P. Recent Pat. Anti-Cancer Drug Discovery 2009, 4, 92.
(3) (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (b) Li, Z.;
Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (c) Basle, O.; Li, C.-J. Green
Chem. 2007, 9, 1047. (d) Li, Z.-P.; Li, C.-J. J. Am. Chem. Soc. 2004, 126,
11810.
(4) (a) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am.
Chem. Soc. 2008, 130, 11005. (b) Murahashi, S.-I.; Takaya, H. Acc.
Chem. Res. 2000, 33, 225. (c) Murahashi, S.-I.; Noata, T. Bull. Chem.
Soc. Jpn. 1996, 69, 1805.
(5) (a) Sud, A.; Sureshkumar, D.; Klussmann, M. Chem. Commun.
2009, 3169. (b) Boess, E.; Sureshkumar, D.; Sud, A.; Wirtz, C.; Fares, C.;
Klussmann, M. J. Am. Chem. Soc. 2011, 133, 8106.
(7) (a) Balzani, V. Electron Transfer in Chemistry; Wiley-VCH:
Weinheim, 2001; Vol. 1. (b) Curran, D. P.; Rakiewicz, D. M. J. Am.
Chem. Soc. 1985, 107, 1448.
(8) For examples of the hazards and reactivity of other radical
initiation systems, see: (a) O’Mahony, G. Synlett 2004, 572. (b) Khattab,
M. A.; Elgamal, M. A.; El-Batouti, M. Fire Mater. 1996, 20, 253. (c)
Molander, G. A. Org. React 1994, 46, 211.
(9) For recent reviews on photoredox catalysis in organic synthesis,
see: (a) Narayanam, J. M. R.; Stephenson, C. R. J. J. Chem. Soc. Rev.
ꢀ
2011, 40, 102. (b) Teply, F. Collect. Czech. Chem. Commun. 2011, 76,
859. (c) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527.
(10) For a representative example of photochemical reactions used as
key steps in natural product syntheses, see: Bach, T.; Hehn, J. P. Angew.
Chem., Int. Ed. 2011, 50, 1000.
(11) For a review on the current synthetic utility of photochemical
processes, see: Albini, A., Fagnoni, M., Eds. Handbook of Synthetic
Photochemistry; Wiley-VCH: Weinheim, 2010.
(6) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang,
Y. M. J. Org. Chem. 2009, 74, 7464.
r
10.1021/ol202883v
Published on Web 12/08/2011
2011 American Chemical Society

stoichiometric oxidants has emerged at the forefront of
this growing trend.12
triethylamine as an example).18 This, in turn, correlates to
a calculatedpKa of the R-CꢀH bond to be 26.7 pKa units.19
By exploiting this inherent physical characteristic of amino
radical cations, we anticipated that we could generate
iminium ions via direct H-atom abstraction or deprotona-
tion and oxidation of the resultant R-amino radical. Due
to several divergent pathways available to the R-amino
radical, and slow catalyst turnover with oxygen, we have
focused upon accelerating the R-CꢀH oxidation chemistry
through modification of the stoichiometric oxidant driven
by our mechanistic observations, thus biasing the pathway
to the iminium ion.20ꢀ22
We began our investigation by choosing a suitable
reaction for optimization, one capable of representing a
broad set of nucleophiles. Based upon this requisite, the
cyanation of tetrahydroisoquinolines was chosen. Our
initial cyanation attempts involved using Ir(ppy)2(dtbbpy)-
PF6 (1 mol %) in N,N-dimethylformamide (DMF) under
white light irradiation (Table 1). Ethyl R-bromoacetate
(EtO2CCH2Br) was chosen as the stoichiometric oxidant
with N-phenyltetrahydroisoquinoline as the substrate and
NaCN as the nucleophile.
Figure 1. Physical properties of amino radical cations and their
potential for diversification under visible-light-mediated photo-
redox catalysis.
In the event, a low isolated yield of the product was
obtained (36%, entry 1). As a result, we switched the
photocatalyst to Ru(bpy)3Cl2 and the light source to blue
LEDs. Diethyl bromomalonate [(Et2OC)2CHBr] was first
selected as the oxidant to probe the reactivity for this
process given the precedented ability of Ru1þ to reduce
the CꢀBr bond. Subsequently, an encouraging 95% iso-
lated yield of cyanation product 2 was obtained (entry 2).
Unfortunately, general application of this oxidant is im-
practical due to its potential side reactivity arising from the
resultant malonyl radical and diethylmalonate generated
after H-atom abstraction. Changing the stoichiometric
oxidant to carbon tetrachloride (CCl4) significantly de-
creased the rate and overall yield, in both DMF and
acetonitrile (CH3CN) (entries 3, 4). In testing the conver-
sion of starting material, BrCCl3 in DMF was found to be
a suitable alternative for catalytic turnover and full con-
version of tetrahydroisoquinoline to the iminium ion was
observed in <3 h (vida infra).
Several synthetic organic groups13ꢀ15 have harnessed the
inherent characteristics of light-active metal complexes such
as Ru(bpy)3Cl2 to promote chemical transformations.16
These metal complexes hold advantages over alternative
reagents for light/energy conversions since their photochem-
ical properties may be fine-tuned through manipulation of
ligand/metal combinations, thus enabling augmentations of
redox potentials.13 As a consequence, a complete overhaul
of reaction design can be avoided.
During our initial investigations into reductive dehalo-
genations using Ru(bpy)3Cl2 in the presence of HCO2H•
iPr2NEt, we discovered, through deuterium labeling experi-
i
ments, that Pr2NEt was a major H-atom donor.17 As
depicted in Figure 1, Ru2þ* (Ered = þ0.84 V vs SCE) is
able to oxidize tertiary amines to generate the correspond-
ing amino radical cation. Accordingly, the bond dissocia-
tion energy (BDE) of the R-CꢀH bond is dramatically
lowered (90.7 kcal/mol BDE drops to ∼17 kcal/mol using
(18) Wayner, D. D. M.; Dannenberg, J. J.; Griller, D. Chem. Phys.
Lett. 1986, 131, 189.
(12) For reviews on the photophysical properties of photoredox
catalysts, see: (a) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.;
Belser, P.; Von Zelewsky, V. Coord. Chem. Rev. 1988, 84, 85. (b)
Kalyanasundaram, K. Coord. Chem. Rev. 1982, 46, 159.
(13) (a) Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2011, 50, 6119 and references therein. (b) Nicewicz, D.;
MacMillan, D. W. C. Science 2008, 322, 77.
(14) (a) Hurtley, A. E.; Cimesia, M. A.; Ischay, M. A.; Yoon, T. P.
Tetrahedron 2011, 67, 4442. (b) Ischay, M. A.; Anzovino, M. E.; Du, J.;
Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12886 and references therein.
(15) (a) Dai, C.; Narayanam, J. M. R.; Stephenson, C. R. J. Nat.
Chem. 2011, 3, 140. (b) Furst, L.; Narayanam, J. M. R.; Stephenson,
C. R. J. Angew. Chem., Int. Ed. 2011, 50, 9655.
(19) See the Supporting Information for pKa approximation derived
from the following: (a) Zhang, X.; Bordwell, F. G. J. Org. Chem. 1992,
57, 4163. (b) Xu, W.; Mariano, P. S. J. Am. Chem. Soc. 1991, 113, 1431.
(c) Dombrowski, G. W.; Dinnocenzo, J. P.; Farid, S.; Goodman, J. L.;
Gould, I. R. J. Org. Chem. 1991, 64, 427. (d) Nelsen, S. P.; Ippoliti, J. T.
J. Am. Chem. Soc. 1986, 108, 4879. (e) Nicholas, M.; de, P.; Arnold,
D. R. Can. J. Chem. 1982, 60, 2165.
ꢀ
ꢀ
(20) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2010, 132, 1464.
(21) For advances in R-CꢀH oxidation of tertiary amines using
photoredox catalysis, see: (a) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang,
N.-J.; Rong, J.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2011, 50,
7171. (b) Xuan, J.; Cheng, Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.; Xiao,
W.-J. Chem. Commun. 2011, 47, 8337. (c) Rueping, M.; Zhu, S.; Koenigs,
R. M. Chem. Commun. 2011, 47, 8679. (d) Rueping, M.; Vila, C.;
Koenigs, R. M.; Poscharny, K.; Fabry, D. C. Chem. Commun. 2011,
47, 2360.
(16) For other selected examples of photoredox catalysis in organic
ꢀ
applications, see: (a) Andrews, R. S.; Becker, J. J.; Gagne, M. R. Org.
Lett. 2011, 13, 2406. (b) Maji, T.; Karmakar, A.; Reiser, O. J. Org.
ꢀ
Chem. 2011, 76, 736. (c) Andrews, S. R.; Becker, J. J.; Gagne, M. R.
Angew. Chem., Int. Ed. 2010, 49, 7274. (d) Koike, T.; Akita, M. Chem.
Lett. 2009, 38, 166.
(17) Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. J. Am.
(22) For a recent example of R-CꢀH oxidation of tertiary amines
using organic dye-mediated photoredox catalysis, see: Hari, D. P.;
€
Chem. Soc. 2009, 131, 8756.
Konig, B. Org. Lett. 2011, 13, 3852.
Org. Lett., Vol. 14, No. 1, 2012
95

Table 1. Optimization of Iminium Ion Formation
Table 2. Functionalization of Tetrahydroisoquinolines
Enabled by Visible-Light-Mediated Photoredox Catalysis
entry
1
conditions
yielda
36
Ir (1 mol %), EtO2CCH2Br (3 equiv),
DMF, white light, NaCN (5 equiv)
Ru (1 mol %), (EtO2C)2CHBr (3 equiv),
DMF, blue LEDs, NaCN (5 equiv)
Ru (1 mol %), CCl4:DMF (1:1),
2
3
4
5
6
7
8
9
95
36
53
60
85
17
NR
83
blue LEDs, NaCN (5 equiv)
Ru (1 mol %), CCl4 (3 equiv), CH3CN,
blue LEDs, NaCN (5 equiv)
Ru (1 mol %), BrCCl3 (3 equiv), DMF,
blue LEDs, NaCN (5 equiv)
Ru (1 mol %), BrCCl3 (3 equiv), DMF,
blue LEDs then no light, NaCN (5 equiv)
Ru (1 mol %), BrCCl3 (3 equiv), DMF,
blue LEDs then no light, Bu4NCN (5 equiv)
Ru (1 mol %), BrCCl3 (3 equiv), THF,
blue LEDs then no light, NaCN (5 equiv)
Ru (1 mol %), BrCCl3 (3 equiv), THF/H2O
(2:1), blue LEDs then no light, NaCN
(5 equiv)
a Isolated percent yields after chromatography on SiO2.
However, reactions with one-pot additions of BrCCl3
and NaCN were found to give inconsistent results and it
was soon discovered that these components reacted under
the photoredox conditions toproduce trichloroacetonitrile
(Cl3CCN), thereby impeding the catalytic cycle. To pre-
vent this undesired reactivity, excess NaCN was added
after TLC analysis indicated full conversion to the
iminium. Furthermore, the reaction flask was removed
from blue LED irradiation. With the use of an inorganic
nucleophile, a solvent screen was then needed to improve
the nucleophilic trapping of more polar reactants. After
evaluation of DMF, CH3CN, and tetrahydrofuran/water
(THF/H2O) mixtures (Table 1, entries 6ꢀ9), the highest
yield was obtained upon using a 2:1 THF/H2O mixture,
providing an 83% yield of cyanation product (entry 9). No
reaction was observed in pure THF presumably due to the
insolubility of the Ru(bpy)3Cl2 catalyst (entry 8).
a Isolated percent yields after chromatography on SiO2. b Ru(bpy)3-
Cl2 (1 mol %), BrCCl3 (3 equiv), DMF, blue LEDs, 3 h, then no light,
Et3N (5 equiv), nitroalkane (5 equiv). c Ru(bpy)3Cl2 (1 mol %), BrCCl3
(3 equiv), DMF, blue LEDs, 3 h, then no light, methallyl trimethylsilane
(5 equiv). d Ru(bpy)3Cl2 (1 mol %), BrCCl3 (3 equiv), DMF, blue LEDs,
3 h, then no light, Et3N (5 equiv), silyl enol ether (5 equiv). e Ru(bpy)3Cl2
(1 mol %), BrCCl3 (3 equiv), DMF, blue LEDs, 3 h, then no light, Et3N
(5 equiv), 1,3-dicarbonyl (5 equiv).
the blue LEDs, we injected a nitroalkane into the reaction
as the nucleophile only to discover slow conversion to
product. However, once we added an equal molar amount
of Et3N23 in the absence of light, the reaction went to
completion under 4 h and the products were isolated in
excellent yield.
Having established our reaction conditions for the suc-
cessful cyanation of N-phenyltetrahydroisoquinoline (1),
we next applied the reaction parameters to a representative
substrate and nucleophile scope. We first assessed the
applicability of our newly developed reaction conditions
to aza-Henry chemistry (Table 2, entries 1ꢀ3).
We further applied our newly developed reaction con-
ditions to other nucleophiles and tetrahydroisoquinolines.
We explored the potential for intermolecular allylations.
Surprisingly, when attempting to trap the iminium with allyl
trimethylsilane, we did not isolate any desired product. We
believe that the putative β-silyl carbocation intermediate is
not stable enough under the conditions to effectively deliver
the desired product. As a result, we tried trapping with
methallyl trimethylsilane, which would undergo addition
via a tertiary carbocation. Fortunately, methallyl trimethyl-
silane addition was successful (Table 2, entries 4ꢀ6).
Surprisingly, after generation of the iminium ion from
the corresponding tetrahydroisoquinoline and removal of
(23) For a discussion on the effects of triethylamine in the electro-
ꢀ
chemical oxidation of N-aryltetrahydroisoquinolines, see: Basle, O.;
Borduas, N.; Dubois, P.; Chapuzet, J. M.; Chan, T.-H.; Lessard, J.;
Li, C.-J. Chem.;Eur. J. 2010, 16, 8162.
96
Org. Lett., Vol. 14, No. 1, 2012

Next, we found that silylenol ethers (Table 2, 12 and 13)
and 1,3-dicarbonyls including malonates and methylaceto-
acetates (Table 2, 14 and 15, respectively) successfully under-
went addition. Acetoacetone also underwent addition;
however, the resulting product readily decomposed upon
purification presumably via a retro-Mannich pathway.
Figure 2. Alkynylation coupled with photoredox catalysis.
ates Ru2þ*, which subsequently oxidizes N-aryltetrahy-
droisoquinoline tothe corresponding radicalcation.24 This
radical cation can then undergo deprotonation to form the
R-amino radical. Oxidation of the R-amino radical by
BrCCl3 (electron transfer or atom transfer) to form the
trichloromethyl radical.25 This radical can then abstract a
H-atom from another N-aryltetrahydroisoquinoline to
generate the R-amino radical and further propagate a
radical chain process.
In conclusion, we have developed a new, more versatile
approach to the functionalization of R-amino carbons
using visible-light-mediated photoredox catalysis. This
method is highlighted by the compatibility of a broad
range of nucleophiles resulting in functionally diverse
products. The use of bromotrichloromethane as the stoi-
chiometric oxidant has successfully promoted the photo-
redox cycle and, in the process, provided insight into the
reaction mechanism. Further exploration of the mecha-
nism and functionalization of R-amino carbons using
visible-light-mediated photoredox catalysis is currently
underway.
Interestingly, we can also use this method to synthesize
polycyclic structures. For example, addition of a siloxyfur-
an following iminium ion formation produced butenolide
16 in good yield (eq 1). Furthermore, exposure of the
iminium to indole results in FriedelꢀCrafts product 17
(eq 2). These diverse nucleophiles provide platforms for
further expansion to more functionalized products.
The products listedinTable 2compare favorably inboth
scope and yield to known methods for their synthesis
including copper-mediated cross-dehydrogenative coupling1
and organic dye photocatalysis.14 However, our reaction
conditions have the capacity to blend two complementary
methods as a means to arrive at diverse functionality.
Figure 2 illustrates this point with the visible-light-mediated
oxidation of N-phenyltetrahydroisoquinolines coupled
with a copper-assisted alkynylation sequence to afford
propargylic amines in good yield.
On the basis of our mechanistic analysis, we believe that
nucleophilic trapping proceeds through the in situ genera-
tion of a reactive iminium ion of N-aryltetrahydroisoqui-
noline (see the Supporting Information). However, we
speculate that formation of the iminium ion can arise via
divergent pathways (see Figure 1). Our first hypothesis
Acknowledgment. Financial support for this research
from the NIH-NIGMS (R01-GM096129), the Alfred
P. SloanFoundation, Amgen, and Boehringer Ingelheim is
gratefully acknowledged. L.F. thanks the Novartis Insti-
tutes for BioMedical Research for a graduate fellowship.
NMR (CHE-0619339) and MS (CHE-0443618) facilities
at BU are supported by the NSF.
involves initial irradiation of Ru2þ to generate Ru2þ
*
which subsequently oxidizes the N-aryltetrahydroisoqui-
noline to the corresponding radical cation. The resulting
Ru1þ, in turn, reduces bromotrichloromethane to the
bromide ion and trichloromethyl radical. H-atom abstrac-
tion by the trichloromethyl radical generates the reactive
iminium ion susceptible to nucleophilic trapping under a
variety of reaction conditions.24
Supporting Information Available. Experimental pro-
cedures, 1H and 13C NMR spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Our second mechanistic hypothesis predicts a radical
chain mechanism where initial irradiation of Ru2þ gener-
(25) For a selected electron transfer/atom transfer case study, see:
Curran, D. P.; Guthrie, D. B.; Geib, S. J. J. Am. Chem. Soc. 2008,
130, 8437.
(24) See the Supporting Information for a detailed mechanism.
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