Bronsted acid cocatalysts in photocatalytic radical addition of α-amino C-H bonds across michael acceptors

Article abstract of DOI:10.1021/jo400428m

In marked contrast to the variety of strategies available for oxidation and nucleophilic functionalization of methylene groups adjacent to amines, relatively few approaches for modification of this position with electrophilic reaction partners have been reported. In the course of an investigation of the reactions of photogenerated α-amino radicals with electrophiles, we made the surprising observation that the efficiency of radical photoredox functionalization of N-aryl tetrahydroisoquinolines is dramatically increased in the presence of a Bronsted acid cocatalyst. Optimized conditions provide high yields and efficient conversion to radical addition products for a range of structurally modified tetrahydroisoquinolines and enones using convenient household light sources and commercially available Ru(bpy)₃Cl ₂ as a photocatalyst. Our investigations into the origins of this unexpected additive effect have demonstrated that the carbon-carbon bond-forming step is accelerated by TFA and is a rare example of Bronsted acid catalysis in radical addition reactions. Moreover, a significant conclusion arising from these studies is the finding that product formation is dominated by radical chain processes and not by photocatalyst turnover. Together, these findings have important implications for the future design and mechanistic evaluation of photocatalytic radical processses.

Full text of DOI:10.1021/jo400428m

Article
pubs.acs.org/joc
Brønsted Acid Cocatalysts in Photocatalytic Radical Addition of
α‑Amino C−H Bonds across Michael Acceptors
Laura Ruiz Espelt, Eric M. Wiensch, and Tehshik P. Yoon*
Department of Chemistry, University of WisconsinMadison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: In marked contrast to the variety of strategies available for
oxidation and nucleophilic functionalization of methylene groups
adjacent to amines, relatively few approaches for modification of this
position with electrophilic reaction partners have been reported. In the
course of an investigation of the reactions of photogenerated α-amino
radicals with electrophiles, we made the surprising observation that the
efficiency of radical photoredox functionalization of N-aryl tetrahy-
droisoquinolines is dramatically increased in the presence of a Brønsted
acid cocatalyst. Optimized conditions provide high yields and efficient
conversion to radical addition products for a range of structurally
modified tetrahydroisoquinolines and enones using convenient household light sources and commercially available Ru(bpy)3Cl2
as a photocatalyst. Our investigations into the origins of this unexpected additive effect have demonstrated that the carbon−
carbon bond-forming step is accelerated by TFA and is a rare example of Brønsted acid catalysis in radical addition reactions.
Moreover, a significant conclusion arising from these studies is the finding that product formation is dominated by radical chain
processes and not by photocatalyst turnover. Together, these findings have important implications for the future design and
mechanistic evaluation of photocatalytic radical processses.
strated that transition metal photoredox catalysts could
effectively oxidize tetrahydroisoquinolines to the corresponding
iminium electrophiles, enabling nucleophilic substitution of the
position adjacent to the amine.4−6 We became curious if
interception of the putative α-amino radical intermediate might
enable the complementary electrophilic functionalization of the
same position under similar photocatalytic conditions.7
INTRODUCTION
■
The α-functionalization of amines has been a challenge of
enduring interest to synthetic chemists (Figure 1).1 It has long
Indeed, while we were conducting our initial explorations of
this hypothesis, Pandey and Reiser reported that the α-amino
radical reactivity of tetrahydroisoquinolines was accessible using
photoredox catalysis (Figure 2).8 In their study, the authors
observed that when a mixture of tetrahydroisoquinoline 5 and
methyl vinyl ketone 6 is irradiated with high-intensity blue LED
lights for 20−24 h in the presence of 5 mol % of [Ir(ppy)2(dtb-
bpy)]PF6 (8·PF6), the radical addition product 7 can be
isolated in 68% yield.9 The same reaction conducted using
commercially available Ru(bpy)3Cl2 (9·Cl2), however, affords a
somewhat lower yield of 7 (58%).
Figure 1. Nucleophilic and electrophilic reactivity accessible from
oxidation of amines.
These results reported by Pandey and Reiser were in accord
with parallel observations made in our own laboratory at the
time. In the process of optimizing for better yields and shorter
reaction times, we have discovered that a Brønsted acid additive
provides a dramatic improvement in the efficiency of this
transformation. As a result, we have been able to design a
photocatalytic radical amine functionalization reaction that can
be conducted using commercially available Ru(bpy)3Cl2 in
been known that a variety of amines undergo facile one-
electron oxidation and that C−H groups adjacent to the
resulting amine radical cations (2) are significantly acidified.
Deprotonation affords α-amino radicals (3), which can undergo
a second one-electron oxidation to produce iminium ions (4)
that are susceptible to attack by a variety of nucleophiles.2,3 The
oxidation of amines to iminium ions has been accomplished
electrochemically,3a,b using stoichiometric oxidants,3c−e photo-
chemically,3f,g and most recently via transition metal catalyzed
oxidation.3d In a seminal contribution, Stephenson demon-
Received: February 27, 2013
Published: March 28, 2013
© 2013 American Chemical Society
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to significantly improve the yield of the reaction (e.g., entry 2).
Similarly, we hoped that base cocatalysts might promote
deprotonation of the amine radical cation,11 but to our surprise,
we observed little effect on the efficiency of the transformation
(entry 3). On the other hand, Brønsted acidic cocatalysts had a
significant but complex impact on the reaction (entries 4−6),
and in particular, the addition of 1 equiv of TFA enabled the
reaction to proceed to completion within 12 h (entry 5). Upon
further optimization, we found that the equivalents of methyl
vinyl ketone could be lowered (entry 7) and that conducting
the reaction at 50 °C provided an excellent yield of the radical
coupling product in just 5 h (entry 8). Control experiments
verified the importance of each reaction component. When the
reaction is conducted at 50 °C without TFA, the yield decreases
dramatically (entry 9). Experiments conducted in the absence
of either photocatalyst or light fail to generate any product
(entries 10 and 11).
Figure 2. Reactions of photocatalytically generated α-amino radicals.8
An exploration of the scope of the radical coupling under
these conditions (Table 2) suggests that N-aryl tetrahydroiso-
quinolines are particularly well suited to this chemistry, in
agreement with the scope of the oxidative functionalization
reactions reported by Stephenson.4 Substrates bearing N-aryl
place of Ir(ppy)2(dtb-bpy)PF6 and convenient household light
sources rather than LEDs. Further, our efforts to understand
the origins of the beneficial effect of the Brønsted acid additive
have resulted in fundamental insights relevant to the catalysis of
radical reactions and to the mechanisms of photocatalytic
processes.
a
Table 2. Reactions of Structurally Varied Amines with 6
RESULTS AND DISCUSSION
■
Our exploratory investigations are summarized in Table 1.
Consistent with the Pandey−Reiser report,8 the photoreaction
a
Table 1. Optimization and Control Studies
b
entry
additive
none
equiv of 6 temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
9
4
4
4
4
4
4
2
2
2
2
2
23
23
23
23
23
23
23
50
50
50
50
12
12
12
12
12
12
12
5
60
68
70
50
88
38
98
96
28
0
NaBF4
NaHCO3
HCO2H
CF3CO2H
TsOH
CF3CO2H
CF3CO2H
none
5
c
10
CF3CO2H
CF3CO2H
5
d
11
5
0
a
Unless otherwise noted, reactions were conducted using 2 mol % of
Ru(bpy)3Cl2 and 1 equiv of additive in degassed MeCN (0.25 M) and
were irradiated using a 23 W compact fluorescent light bulb at a
b
1
distance of 30 cm. Yields determined by H NMR using an internal
c
standard. Reaction conducted in the absence of Ru(bpy)3Cl2.
Reaction conducted in the dark.
d
a
Unless otherwise noted, reactions were conducted using 2 mol % of
Ru(bpy)3Cl2, 2 equiv of MVK, and 1 equiv of TFA in degassed MeCN
of 5 and 6 in the presence of Ru(bpy)3Cl2 was sluggish and
stalled before complete consumption of 5 (entry 1). We
speculated that increasing the ionic strength of the solution
might support formation of the charged radical cation
intermediate;10 however, addition of various electrolytes failed
(0.25 M) at 50 °C and were irradiated using a 23 W compact
b
fluorescent light bulb at a distance of 30 cm. Values represent the
averaged isolated yields of two reproducible experiments unless
c
1
otherwise noted. Yield determined by H NMR using an internal
standard.
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moieties of varying electronic nature react in high yields
(entries 1−4), although ortho-substituted N-arenes significantly
retard the rate of reaction (entry 5). The isoquinoline ring
system, similarly, can tolerate both electron-donating and
electron-withdrawing substitution (entries 6 and 7). However,
N-alkyl-substituted isoquinolines do not react under these
conditions, and other heterocyclic N-arylamines exhibit
diminished reactivity (entry 8).
Both aliphatic and aromatic enones react efficiently (entries 1
and 2). Acrylate esters also participate but with poor efficiency,
consistent with their lower electrophilicity (entry 3). Aldehydes
are excellent reaction partners and provide very high yields of
the product in low reaction times (entries 4 and 5).
Unfortunately, reactions with substituted enones provide little
diastereocontrol (entry 5), and β-substituted enones react at
significantly diminished rates (entry 6).
Experiments exploring the generality of the reaction with
respect to the Michael acceptor are summarized in Table 3.
Collectively, these results indicate that the use of the TFA
additive confers several practical benefits. The photocatalytic
radical functionalization of tetrahydroisoquinolines is markedly
more efficient in the presence of the Brønsted acid cocatalyst,
providing uniformly higher yields with shorter reaction times.
In addition, these conditions utilize a commercially available
Ru(bpy)32+ photocatalyst in place of the more precious iridium
chromophore and a standard household light bulb in place of a
high-intensity monochromatic blue LED strip.
Table 3. Reactions of Michael Acceptors with
a
Tetrahydroisoquinoline 5
The most intriguing aspect of this reaction, however, is the
unexpected beneficial effect of TFA. In addition to providing
higher yields of the desired product, this additive also
accelerated the radical coupling reaction and reduced the
formation of undesired side products. To better understand
these results, we elected to study the origins of this dramatic
Brønsted acid effect in greater detail.
Mechanistic Studies. We first performed a qualitative
analysis of the progress of the room-temperature reaction
between tetrahydroisoquinoline 5 and enone 10, both in the
presence and absence of the TFA additive. These data are
summarized in Figure 3. In the presence of TFA, the reaction is
complete within 6 h, and the starting tetrahydroisoquinoline is
cleanly converted to the radical addition product in high yield.
On the other hand, the reaction conducted in the absence of
TFA appeared to proceed at a slower initial rate and stall after
1
a
approximately 8 h of irradiation. Moreover, H NMR analysis
Unless otherwise noted, reactions were conducted using 2 mol % of
Ru(bpy)3Cl2, 2 equiv of MVK, and 1 equiv of TFA in degassed MeCN
(0.25 M) at 50 °C and were irradiated using a 23 W compact
fluorescent light bulb at a distance of 30 cm. Values represent the
of the reaction mixture revealed the formation of a number of
side products that were not observed in the TFA-promoted
reaction. Thus, the TFA additive appears to improve the initial
rate of product formation, prevent the formation of undesirable
side products, and avoid a catalyst deactivation pathway.
We next investigated the relationship between the pKa of the
Brønsted acid additive and the yield of the reaction (Figure 4).
b
averaged isolated yields of two reproducible experiments unless
c
d
otherwise noted. Diastereomer ratios determined by 1H NMR. Yield
1
determined by H NMR using an internal standard.
Figure 3. Reaction progress in the absence and presence of TFA.
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Figure 4. Relationship between cocatalyst acidity and efficiency of the
radical coupling of 5 and 6. Reactions conducted using 2 mol % of
Ru(bpy)3Cl2, 2 equiv of MVK, and 1 equiv of acid in degassed MeCN
(0.25 M) at room temperature under irradiation by a 23 W compact
fluorescent bulb at 30 cm.
Figure 6. Kinetic isotope effects.
The formation of 7 was most efficient within a relatively narrow
range of acidity (pKa ∼ 1). Additives of both greater and weaker
acidity were less effective, and very strong acids inhibited the
reaction completely. In the high pKa regime, the observation
that stronger acids result in higher yields is consistent with the
interpretation that the Brønsted acid is a cocatalyst for the
formation of 7. Brønsted acid inhibition in the low pKa range is
also reasonably easy to rationalize. The formation of the key α-
amino radical requires the availability of free amine; in the
presence of strong acids such as TfOH, the protonated
Finally, we investigated the effect of isotopic labeling of the
each of the coupling partners (Figure 6). To facilitate
measurement of kinetic isotope effects (KIE) by GC, we
examined labeled and unlabeled reactions of isoquinoline 5
with 2-phenylethyl enone 10. In the absence of the TFA
cocatalyst, the KIE associated with amine 5 was negligible;
however, we observed an inverse second-order KIE with
respect to the enone. Addition of TFA to the reaction
conditions, on the other hand, gave significantly different
results. We measured a first-order KIE with respect to the
amine and a normal second-order KIE with respect to the
enone. Interpretation of the magnitude of these isotope effects
is challenging due to the presence of multiple equilibria and
because there is presumably some contribution of the
uncatalyzed reaction to the formation of products even in the
presence of TFA. Nevertheless, these data strongly suggest that
the rate determining step changes upon addition of the
Brønsted acid cocatalyst.
2+
ammonium cannot be photoxidized by Ru*(bpy)3 to initiate
the reaction. On the other hand, we propose that weaker acid
cocatalysts results in an equilibrium concentration of free amine
2+
sufficient to participate in reductive quenching of Ru*(bpy)3
.
In support of this hypothesis, we examined the reaction of 5
and 6 in the presence of varying concentrations of TFA and
found that the efficiency of these reactions were comparable
within a dynamic range of 0.5−2 equiv of TFA, while higher
concentrations of acid completely inhibited product forma-
tion.12 Consistent with these results, we performed a titration
of isoquinoline 5 with TFA and observed that 1H NMR analysis
showed saturation behavior, which presumably corresponds to
quantitative formation of the unreactive ammonium TFA salt
(Figure 5).
We interpreted the results of these experiments in the
context of the mechanistic hypothesis proposed in Scheme 1,
which is quite similar to the mechanism proposed by Pandey
and Reiser. Oxidation of the amine by the excited photocatalyst
2+
Ru*(bpy)3 would produce radical cation 12. Subsequent
deprotonation of this intermediate would form the key α-amino
radical 13, which can then react with the Michael acceptor to
form radical adduct 16. The observed product 7 would be
generated from the α-keto radical species 16 by one of two
possible pathways: either a chain-propagating hydrogen atom
abstraction (path IV) of tetrahydroisoquinoline 5 or chain-
+
terminating electron transfer from the reduced Ru(bpy)3
photocatalyst (path V). Several of these steps could potentially
be rate-limiting, and we considered the effect Brønsted acid
additives could have on each of them in turn.
First, we evaluated the step involving oxidation of the amine
(step I in Scheme 1). The rates of reductive quenching of
Ru*(bpy)32+ by a variety of tertiary anilines have been studied.
These are generally quite fast and can be close to the diffusion-
controlled limit.13 This step is thus unlikely to be responsible
for the slow rate of the overall reaction. Moreover, the
observation that the formation of the ammonium salt inhibits
product formation is also inconsistent with the contention that
Brønsted acids could accelerate of this step.
1
Figure 5. H NMR titration of 5 with TFA.
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Scheme 1
Similarly, we also considered the deprotonation of the
tetrahydroisoquinoline radical cation (step II). Amine radical
cations are generally considered to be quite acidic, although
various reports have raised doubts about this common
assumption.14 Nevertheless, it does not seem reasonable to
suppose that the Brønsted acid accelerates this deprotonation
step. We can also rule out the possibility that TFA accelerates
this step via a solvent polarity effect because the addition of
ionic electrolytes has a negligible effect on the reaction (e.g.,
Table 1, entry 2). Moreover, we observe a kinetic isotope effect
with respect to the enone under both acid-catalyzed and acid-
free conditions; it must be the case that the enone is involved in
the rate-determining step of this transformation under both sets
of conditions.
benefits this reaction both by accelerating the slow carbon−
carbon bond-forming step and by keeping the concentration of
13 so low that this catalyst-deactivating dimerization step
becomes insignificant.
These findings have a number of important implications. The
first is that TFA is capable of lowering the kinetic barrier for
addition of the nucleophilic α-amino radical to the enone, to
the point that step III becomes no longer rate-limiting in this
process. Although the ability of Lewis acids to accelerate the
addition of nucleophilic radicals to Michael acceptors has been
of significant recent interest,15 only a few reports have
suggested the ability of Brønsted acids to catalyze similar
radical additions.16 We expect that this observation could have
important implications in the design of other radical addition
reactions.
The data suggest that the addition of the acid cocatalyst
results in a change of the rate-determining step. When reactions
are performed without added TFA, the data are most consistent
with rate-limiting addition of α-amino radical 13 to the enone
(step III). The observation of an inverse secondary KIE upon
deuteration of the enone under these conditions supports this
interpretation. When the reaction is conducted in the presence
of TFA, however, the normal secondary KIE with respect to the
enone and the primary KIE with respect to the tetrahydroiso-
quinoline suggests that the rate-limiting step involves chain-
propagating hydrogen atom abstraction from 5 by α-keto
radical 16 (step IV). Rate-limiting photocatalyst turnover (step
V) cannot be the dominant pathway of product formation
because it would not result in the observed primary KIE for 5.
This interpretation also explains the observation that
tetrahydroisoquinoline dimer 14 is an observable byproduct
only in the absence of TFA. A consequence of rate-limiting
addition into the enone would be buildup of the concentration
of α-amino radical 13, at which point the rate of dimerization to
14 would become non-negligible. This termination step is
problematic for the photocatalytic process because it provides
no opportunity for turnover of the reduced photocatalyst,
which would accumulate in its photochemically inactive
A second implication of this study is that chain propagation,
and not catalyst turnover, is the process dominating the kinetics
of product formation.17 The importance of radical chain
mechanisms in photoinduced radical addition reactions has
been well documented by Fagnoni18 and Hoffmann19 using
organic photosensitizers. We believe that chain processes may
also be a common feature of many of the recent reports of free
radical transformations initiated by photoredox catalysis.20
+
Scheme 1 suggests that Ru(bpy)3 is generated by reductive
quenching of the excited photocatalyst with 5 to generate the
corresponding amine radical cation. Thus, the total concen-
tration of all radical species in solution at any given point
+
should be no greater than the concentration of Ru(bpy)3 ,
which in turn can be no greater than the initial concentration of
2+
the Ru(bpy)3 photocatalyst. In reactions using catalytic
loadings of the photocatalyst, therefore, the rate of bimolecular
+
interaction of Ru(bpy)3 and α-keto radical 16 will be
constrained by the low concentrations of these two species,
and it is reasonable to hypothesize that radical chain
propagation might be the dominant pathway for product
formation for many mechanistically analogous photoredox
reactions. Indeed, the participation of productive chain
+
Ru(bpy)3 oxidation state. The addition of TFA therefore
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solid (780 mg, 75% yield): IR (thin film) 3057, 1652, 1415, 1221, 741
processes may account for the low loadings of photocatalyst
that can be used in many reported photoredox processes.
1
cm−1; H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz, 1H), 7.47
(td, J = 7.6, 1.3 Hz, 1H), 7.40 (m, 5H), 7.25 (m, 2H), 4.00 (t, J = 6.6
Hz, 2H), 3.15 (t, J = 6.6 Hz, 2H); 13C NMR (125 MHz, CDCl3)
164.2, 143.1, 138.3, 132.0, 129.7, 128.9, 128.8, 127.2, 126.9, 126.2,
125.3, 49.4, 28.6; HRMS (EI+) calcd for [C15H13NO]+ requires m/z
223.0992, found m/z 223.0989; mp = 102 °C.
CONCLUSION
■
We may draw several conclusions from the observation that
Brønsted acid additives can provide a significant improvement
in the efficiency of the radical functionalization of the α-amino
C−H bond of a variety of tetrahydroisoquinolines. From a
practical synthetic perspective, we have shown that the rates
and yields of this process can be significantly improved, and
that these conditions enable excellent conversion using
1,1-Dideutero-2-phenyl-1,2,3,4-tetrahydroisoquinoline (5-
d2). To a stirred suspension of LiAlD4 (82 mg, 2.0 mmol) in 20 mL
of THF was added 2-phenyl-3,4-dihydroisoquinolin-1(2H)-one under
an argon atmosphere. After being refluxed for 2 h, the mixture was
cooled to 0 °C and quenched with water. The product was extracted
with eight portions of Et2O. The combined organics were then washed
with brine, dried over MgSO4, and concentrated in vacuo. Purification
by chromatography on silica gel using 4:1 hexanes:EtOAc as the eluent
afforded the product as a white solid (360 mg, 95% yield): IR (thin
film) 3023, 2963, 1660, 1598, 1109, 1049 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.28 (m, 2H), 7.16 (m, 4H), 6.98 (dt, J = 7.9, 0.9 Hz, 2H),
6.82 (tt, J = 7.2, 1.1 Hz, 1H), 3.56 (t, J = 5.8 Hz, 2H), 2.98 (t, J = 5.8
Hz, 2H); 13C NMR (125 MHz, CDCl3) 149.5, 133.9, 133.3, 128.2,
127.5, 125.5, 125.3, 125.0, 117.6, 114.1, 49.0 (t, J = 21.0 Hz), 45.4,
28.1; HRMS (ESI+) calcd for [C15H13D2N + H]+ requires m/z
212.1413, found m/z 212.1407; mp = 45 °C.
2+
commercially available Ru(bpy)3 in place of a precious
third-row transition metal photocatalyst, and a household light
bulb instead of a high-intensity monochromatic LED light
source. From this study and many others, it is apparent that
there is a synergistic benefit of combining various cocatalysts
with photoredox catalysts.21
Our investigations into the origin of this dramatic additive
effect have demonstrated that the key carbon−carbon bond-
forming step is accelerated by TFA and is a rare example of
Brønsted acid catalysis in radical addition reactions. We
anticipate that the rational application of this concept in
other contexts will facilitate the discovery of new synthetically
useful radical addition reactions. Our investigations also
document the participation of chain-propagation events in
this transformation and suggest that the mechanism of other
radical reactions initiated by photoredox catalysis may be more
complicated than generally appreciated. We are continuing to
probe these possibilities in ongoing studies in our laboratory.
1,1,2-Trideutero-5-phenylpent-1-en-3-one (10-d3). To a
solution of 4-phenyl-1-(triphenylphosphoranylidene)butan-2-one (2
g, 4.9 mmol) in 10 mL of DCM was added 20% formaldehyde-d2
solution in D2O (3.9 mL, 24.5 mmol). The reaction mixture was
stirred at room temperature overnight and extracted twice with DCM.
The combined organics were then washed with brine, dried over
MgSO4, and concentrated in vacuo. Purification of the residue by
chromatography on silica gel using 20:1 hexanes/EtOAc as the eluent
afforded the product as a yellow oil (342 mg, 52% yield): IR (thin
1
film) 3030, 2927, 2363, 1681, 1551, 1496, 1451 cm−1; H NMR (500
MHz, CDCl3) δ 7.29 (m, 2H), 7.21 (m, 3H), 2.94 (m, 4H); 13C NMR
(125 MHz, CDCl3) 199.8, 141.1, 136.0 (t, J =, 24.3 Hz), 128.5, 128.4,
127.6 (q, J = 24.5 Hz), 127.4, 127.2, 126.2, 41.2, 29.7; HRMS (ESI+)
calcd for [C15H13D2N + H]+ requires m/z 163.1071, found m/z
163.1073.
EXPERIMENTAL SECTION
■
2-(o-Tolyl)-1,2,3,4-tetrahydroisoquinoline. A 25 mL round-
bottomed flask was charged with Pd2(dba)3 (20.6 mg, 0.02 mmol),
BINAP (28.6 mg, 0.05 mmol), and 3 mL of toluene. The resulting
solution was degassed by sparging with argon for 10 min before being
heated to 110 °C for 15 min. The reaction mixture was allowed to cool
to room temperature before NaO-t-Bu (100.5 mg, 1.1 mmol), 2-
bromotoluene (191.4 mg, 1.1 mmol), and 1,2,3,4,-tetrahydroisoquino-
line (300 mg, 2.2 mmol) were added. The resulting mixture was
heated to reflux for 20 h before being cooled to room temperature and
filtered through a pad of Celite. Solvents were removed under reduced
pressure, and the residue was purified by chromatography on silica gel
using 30:1 hexanes/EtOAc as the eluent to afford the product as a
yellow oil (136 mg, 27% yield): IR (thin film) 3020, 2918, 1492, 1446,
1379, 1107 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.16 (m, 5H), 7.07
(m, 2H), 6.99 (td, J = 7.4, 1.2 Hz, 1H), 4.10 (s, 2H), 3.19 (t, J = 5.8
Hz, 2H), 2.99 (t, J = 5.8 Hz, 2H), 2.33 (s, 3H); 13C NMR (125 MHz,
CDCl3) 151.5, 135.4, 134.6, 132.9, 131.1, 128.9, 126.6, 126.4, 126.1,
125.7, 123.2, 119.3, 54.2, 50.3, 29.7, 18.0; HRMS (ESI+) calcd for
[C16H17N + H]+ requires m/z 224.1434, found m/z 224.1434.
2-Phenyl-3,4-dihydroisoquinolin-1(2H)-one. After three cycles
of evacuation and backfilling with dry nitrogen, an oven-dried Schlenk
tube equipped with a magnetic stirring bar was charged with 3,4-
dihydroisoquinolin-1(2H)-one22 (700 mg, 4.8 mmol), CuI (38 mg, 0.2
mmol), K2PO4 (7.8 g, 1.7 mmol), and iodobenzene (0.8 mL, 3.9
mmol). The tube was evacuated and backfilled with nitrogen, and then
2,2,6,6-tetramethyl-3,5-heptanedione (72 mg, 0.39 mmol) and
anhydrous degassed toluene (4 mL) were added under a stream of
nitrogen by syringe at room temperature. The tube was sealed under a
positive pressure of nitrogen, stirred, and heated to 130 °C for 24 h.
After being cooled to room temperature, the reaction was diluted with
100 mL of CH2Cl2 and washed twice with water. The aqueous phases
were extracted five times with dichloromethane. The organic layers
were combined, dried over MgSO4, filtered, and concentrated under
vacuum. Purification of the residue by chromatography on silica gel
using 4:1 hexanes/EtOAc as the eluent afforded the product as a white
General Procedure for Photochemical Reactions. A dry 25
mL Schlenk tube was charged with the amine (1 equiv), Michael
acceptor (2 equiv), Ru(bpy)3Cl2·6H2O (0.02 equiv), TFA (1 equiv),
and acetonitrile (0.25 M) and degassed using three freeze/pump/thaw
cycles under nitrogen in the dark. The reaction was then heated in an
oil bath at 50 °C and allowed to stir while being irradiated by a 23 W
(1280 lm) compact fluorescent lamp at a distance of 30 cm. Upon
completion of the reaction, the mixture was allowed to cool to room
temperature, neutralized with K2CO3 (2 equiv), and filtered through a
small plug of silica with Et2O. Removal of the solvent in vacuo afforded
analytically pure product.
4-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one
(Table 2, entry 1): colorless oil; experiment 1, 120 mg (0.43 mmol,
90% yield); experiment 2, 116 mg (0.42 mmol, 89% yield): IR (thin
film) 3060, 2923, 1712, 1597, 1503, 1159 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.21 (m, 2H), 7.14 (m, 3H), 7.08 (m, 1H), 6.87 (d, J = 8.4
Hz, 2H), 6.73 (t, J = 7.0 Hz, 1H), 4.72 (dd, J = 9.1, 5.5 Hz, 1H), 3.59
(m, 1H), 3.54 (m, 1H), 2.98 (m, 1H), 2.74 (dt, J = 16.3, 4.6 Hz, 1H),
2.55 (t, J = 7.1 Hz, 2H), 2.21 (m, 1H), 2.07 (s, 3H), 2.04 (m, 1H); 13C
NMR (125 MHz, CDCl3) 149.8, 138.3, 134.9, 129.3, 128.8, 127.2,
126.5, 125.9, 117.7, 114.6, 57.9, 41.5, 40.3, 30.3, 30.2, 26.3; HRMS
(ESI+) calcd for [C19H21NO + H]+ requires m/z 280.1696, found m/z
280.1704.
4-(2-(p-Tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-one
(Table 2, entry 2): white solid; experiment 1, 128 mg (0.44 mmol, 98%
yield); experiment 2, 124 mg (0.42 mmol, 97% yield); IR (thin film):
1
3022, 2919, 2247, 1712, 1616, 1517, 909 cm−1; H NMR (500 MHz,
CDCl3) δ 7.13 (m, 3H), 7.05 (d, J = 6.9 Hz, 1H), 7.01 (d, J = 8.3 Hz,
2H), 6.79 (dt, J = 9.0, 2.9 Hz, 2H), 4.63 (dd, J = 9.5, 5.3 Hz, 1H), 3.56
(m, 1H), 3.50 (m, 1H), 2.95 (m, 1H), 2.67 (dt, J = 16.2, 4.2 Hz, 1H),
2.55 (t, J = 6.9 Hz, 2H), 2.23 (s, 3H), 2.18 (m, 1H), 2.07 (s, 3H), 2.03
(m, 1H); 13C NMR (125 MHz, CDCl3) 208.6, 147.9, 138.5, 134.9,
4112
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129.8, 128.8, 127.4, 127.3, 126.4, 125.9, 115.4, 58.1, 41.8, 40.4, 30.5,
30.3, 26.0, 20.3; HRMS (ESI+) calcd for [C20H23NO + H]+ requires
m/z 294.1853, found m/z 294.1853.
(m, 2H), 7.06 (d, J = 6.7 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.78 (d, J
= 8.1 Hz, 2H), 4.75 (dd, J = 9.4, 4.3 Hz, 1H), 3.57 (m, 2H), 3.09 (m,
2H), 2.96 (m, 1H), 2.69 (dt, J = 16.5, 5.3 Hz, 1H), 2.35 (m, 1H), 2.24
(m, 1H), 2.20 (s, 3H); 1 3C NMR (125 MHz, CDCl3) 200.1, 147.9,
138.5, 137.1, 134.9, 132.8, 129.7, 128.8, 128.5, 128.0, 127.4, 126.4,
125.9, 115.6, 58.4, 42.0, 35.5, 31.0, 26.1, 20.3; HRMS (ESI+) calcd for
[C25H25NO + H]+ requires m/z 356.2009, found m/z 356.2012.
3-(2-(p-Tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)propanal (Table
3, entry 4): white solid; experiment 1, 117 mg (0.42 mmol, 94% yield);
experiment 2, 121 mg (0.43 mmol, 97% yield); IR (thin film) 3063,
2920, 2246, 1719, 1616, 1517, 909 cm−1; 1H NMR (500 MHz,
CDCl3) δ 9.70 (t, J = 1.4 Hz, 1H), 7.14 (m, 3H), 7.06 (d, J = 6.9 Hz,
1H), 7.02 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 4.61 (dd, J =
10.1, 5.3 Hz, 1H), 3.52 (m, 2H), 2.92 (m, 1H), 2.65 (dt, J = 16.0, 4.5
Hz, 1H), 2.52 (m, 2H), 2.28 (m, 1H), 2.23 (s, 3H), 2.11 (m, 1H); 13C
NMR (125 MHz, CDCl3) 201.7, 147.7, 137.9, 135.0, 129.8, 128.9,
128.2, 127.2, 126.5, 126.0, 116.3, 58.4, 42.5, 41.1, 29.8, 25.9, 20.3;
HRMS (ESI+) calcd for [C19H21NO + H]+ requires m/z 280.1696,
found m/z 3280.1706; mp = 66 °C.
2-Methyl-3-(2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-
propanal (Table 3, entry 5): inseparable 1:1.5 mixture of
diastereomers, colorless oil; experiment 1, 120 mg (0.41 mmol, 91%
yield); experiment 2, 124 mg (0.43 mmol, 94% yield); IR (thin film)
2965, 2922, 2247, 1719, 1615, 1513, 1038 cm−1; 1H NMR (500 MHz,
CDCl3) major diastereoisomer δ 9.58 (d, J = 1.1 Hz, 1H), 6.99−7.18
(m, 6H), 6.76 (dt, J = 8.7, 2.9 Hz, 2H), 4.69 (dd, J = 9.8, 4.7 Hz, 1H),
3.49 (m, 2H), 2.86 (m, 1H), 2.43- 2.66 (m, 3H), 2.22 (s, 3H), 2.15
(m, 1H), 1.14 (d, J = 6.9 Hz, 3H); minor diastereomer d 9.57 (d, J =
2.5 Hz, 1H), 6.99- 7.18 (m, 6H), 6.80 (dt, J = 8.7, 2.7 Hz, 2H), 4.61
(dd, J = 10.8, 4.6 Hz, 1H), 3.49 (m, 2H), 2.86 (m, 1H), 2.43- 2.66 (m,
2H), 2.22 (s, 3H), 2.21 (m, 1H), 1.74 (dt, J = 1.45, 4.9 Hz, 1H), 1.11
(d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) 203.8, 203.4, 147.7,
138.0, 137.8, 135.0, 134.9, 129.8, 129.7, 129.1, 129.0, 128.8, 128.8,
127.2, 126.5, 126.4, 126.0, 126.0, 117.3, 117.3, 57.5, 55.5, 44.8, 43.5,
43.0, 42.4, 39.9, 38.6, 25.4, 25.0, 20.4, 14.6, 13.5; HRMS (ESI+) calcd
for [C20H23NO + H]+ requires m/z 294.1853, found m/z 294.1864.
1-Phenyl-5-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)pentan-
3-one (11). The yields represented here are 1H NMR yields, calculated
from the crude against an internal standard. A clean sample of the
product was obtained by using a 1:1 mixture of starting material and
acceptor. The data for that sample is shown below: white solid;
experiment 1, 94% yield; experiment 2, 97% yield; IR (thin film) 3030,
2927, 2360, 1713, 1601, 1501, 1398 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.27−7.07 (m, 11H), 6.86 (d, J = 7.9 Hz, 2H), 6.73 (t, J =
6.7 Hz, 1H), 4.71 (dd, J = 9.6, 5.7 Hz, 1H), 3.56 (m, 2H), 2.98 (m,
1H), 2.85 (t, J = 8.3 Hz, 2H), 2.73 (dt, J = 16.6, 4.7 Hz, 1H), 2.65 (m,
2H), 2.51 (t, J = 6.7 Hz, 2H), 2.24 (m, 1H), 2.05 (m, 1H); 13C NMR
(125 MHz, CDCl3) 209.6, 149.8, 141.1, 138.3, 134.9, 129.4, 128.8,
128.5, 128.3, 127.3, 126.5, 126.1, 125.9, 117.8, 114.6, 58.0, 44.6, 41.4,
39.7, 30.4, 29.7, 26.3; HRMS (ESI+) calcd for [C26H27NO + H]+
requires m/z 370.2166, found m/z 370.2177; mp = 114 °C.
4-(2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-
butan-2-one (Table 2, entry 3): white solid; experiment 1, 120 mg
(0.39 mmol, 93% yield); experiment 2, 124 mg (0.40 mmol, 96%
1
yield); IR (thin film) 2997, 2950, 1711, 1509, 1037 cm−1; H NMR
(500 MHz, CDCl3) δ 7.16 (m, 2H), 7.13 (m, 1H), 7.06 (d, J = 7.0 Hz,
1H), 6.84 (dt, J = 8.6, 2.5 Hz, 2H), 6.78 (dt, J = 9.2, 2.3 Hz, 2H), 4.51
(dd, J = 10.2, 4.4 Hz, 1H), 3.73 (s, 3H), 3.48 (dd, J = 7.6, 4.4 Hz, 2H),
2.89 (m, 1H), 2.63 (dt, J = 16.3, 4.2 Hz, 1H), 2.55 (td, J = 7.3, 2.1 Hz,
2H), 2.17 (m, 1H), 2.08 (s, 3H), 2.03 (m, 1H); 13C NMR (125 MHz,
CDCl3) 208.8, 152.9, 144.6, 138.4, 134.9, 128.9, 127.2, 126.3, 125.9,
118.2, 114.6, 58.7, 55.6, 43.0, 40.4, 30.6, 30.3, 25.8; HRMS (ESI+)
calcd for [C20H23NO2 + H]+ requires m/z 310.1802, found m/z
310.1817.
4-(2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-
2-one (Table 2, entry 4): white solid. Experiment 1: 133 mg (0.42
mmol, 99% yield). Experiment 2: 133 mg (0.42 mmol, 99% yield). IR
(thin film): 2923, 2847, 1712, 1594, 1496, 1159 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.15 (m, 5H), 7.10 (m, 1H), 6.79 (dt, J = 9.5, 3.2 Hz,
2H), 4.66 (dd, J = 9.4, 4.9 Hz, 1H), 3.54 (dd, J = 7.2, 4.9 Hz, 2H), 2.96
(m, 1H), 2.77 (dt, J = 16.2, 4.7 Hz, 1H), 2.53 (t, J = 7.1 Hz, 2H), 2.20
(m, 1H), 2.09 (s, 3H), 2.02 (m, 1H); 13C NMR (125 MHz, CDCl3)
208.4, 137.9, 134.7, 129.1, 128.8, 127.2, 126.7, 126.0, 122.4, 115.6,
58.0, 41.8, 40.2, 30.2, 30.2, 26.3; HRMS (ESI+) calcd for
[C19H20ClNO + H]+ requires m/z 314.1307, found m/z 314.1322.
4-(6,7-Dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-
butan-2-one (Table 2, entry 6): colorless oil; experiment 1, 120 mg
(0.35 mmol, 95% yield); experiment 2, 123 mg (0.36 mmol, 98%
1
yield); IR (thin film) 2999, 2935, 2252, 1710, 1597, 1249 cm−1; H
NMR (500 MHz, CDCl3) δ 7.21 (td, J = 7.7, 1.8 Hz, 2H), 6.87 (d, J =
8.0 Hz, 2H), 6.73 (t, J = 7.4 Hz, 1H), 6.67 (s, 1H), 6.56 (s, 1H), 4.65
(dd, J = 9.8, 4.9 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.65 (dt, J = 13.1,
4.6 Hz, 1H), 3.50 (m, 1H), 2.91 (m, 1H), 2.58 (m, 3H), 2.16 (m, 1H),
2.09 (s, 3H), 2.04 (m, 1H); 13C NMR (125 MHz, CDCl3) 208.8,
150.1, 147.6, 147.3, 130.3, 129.3, 126.7, 118.0, 115.1, 111.5, 110.2,
57.6, 56.0, 55.8, 41.3, 40.3, 30.3, 30.3, 25.5; HRMS (ESI+) calcd for
[C21H25NO3 + H]+ requires m/z 340.1908, found m/z 340.1920.
4-(7-Chloro-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-
one (Table 2, entry 7): colorless oil; experiment 1, 123 mg (0.39
mmol, 96% yield); experiment 2, 122 mg (0.38 mmol, 95% yield); IR
1
(thin film) 2924, 1711, 1599, 1507, 749, 693 cm−1; H NMR (500
MHz, CDCl3) δ 7.21 (m, 3H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 7.00 (d,
J = 8.2 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 7.2 Hz, 1H), 4.68
(dd, J = 9.2, 5.4 Hz, 1H), 3.64 (dt, J = 13.3, 4.2 Hz, 1H), 3.49 (tt, J =
10.4, 4.6 Hz, 1H), 2.92 (m, 1H), 2.64 (dt, J = 16.3, 3.7 Hz, 1H), 2.57
(t, J = 6.7 Hz, 2H), 2.18 (m, 1H), 2.09 (s, 3H), 2.05 (m, 1H); 13C
NMR (125 MHz, CDCl3) 208.3, 149.7, 140.2, 133.2, 131.4, 130.2,
129.4, 127.1, 126.6, 118.3, 115.1, 57.7, 41.1, 40.2, 30.3, 25.4; HRMS
(ESI+) calcd for [C19H20ClNO + H]+ requires m/z 314.1307, found
m/z 314.1303.
ASSOCIATED CONTENT
* Supporting Information
1-(2-(p-Tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)pentan-3-one
(Table 3, entry 1): colorless oil; experiment 1, 135 mg (0.44 mmol,
98% yield); experiment 2, 137 mg (0.45 mmol, 99% yield); IR (thin
■
S
Experimental details for kinetic and NMR titration studies and
spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
film): 3023, 2975, 2249, 1710, 1615, 1517, 909 cm−1; H NMR (500
MHz, CDCl3) δ 7.14 (m, 2H), 7.11 (m, 1H), 7.05 (d, J = 7.0 Hz, 1H),
7.01 (d, J = 8.4 Hz, 2H), 6.78 (dt, J = 8.7, 3.1 Hz, 2H), 4.64 (dd, J =
9.8, 5.4 Hz, 1H), 3.55 (m, 1H), 3.51 (m, 1H), 2.94 (m, 1H), 2.66 (dt, J
= 16.8, 4.3 Hz, 1H), 2.52 (t, J = 6.7 Hz, 2H), 2.35 (m, 2H), 2.22 (s,
3H), 2.18 (m, 1H), 2.06 (m, 1H), 1.01 (t, 3H); 13C NMR (125 MHz,
CDCl3) 211.4, 147.8, 138.5, 134.9, 129.8, 128.8, 127.3, 126.4, 125.8,
115.4, 58.2, 41.7, 39.1, 36.1, 30.5, 26.0, 20.3, 7.8; HRMS (ESI+) calcd
for [C21H25NO + H]+ requires m/z 308.2009, found m/z 308.2004.
1-Phenyl-3-(2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-
propan-1-one (Table 3, entry 2): white solid; experiment 1, 143 mg
(0.40 mmol, 90% yield); experiment 2, 146 mg (0.41 mmol, 92%
yield); IR (thin film) 3061, 3025, 2247, 1682, 1615, 1517, 999 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 7.6 Hz, 2H), 7.50 (t, J =
AUTHOR INFORMATION
Corresponding Author
*E-mail: tyoon@chem.wisc.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Bob Bergman and Prof. Clark Landis for helpful
discussions concerning the mechanism of this process. We are
grateful for funding from the NIH (GM095666) and the Sloan
7.6 Hz, 1H), 7.39 (t, J = 8.1 Hz, 2H), 7.21 (d, J = 6.7 Hz, 1H), 7.14
4113
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The Journal of Organic Chemistry
Article
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Foundation. E.M.W. is the recipient of a Hilldale Fellowship
from UWMadison. The NMR facilities at UWMadison are
funded by the NSF (CHE-1048642) and a generous gift from
Paul J. Bender.
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