Dehydrogenative functionalization of C(sp3)-H bonds adjacent to a heteroatom mediated by oxoammonium salts

Article abstract of DOI:10.1002/ejoc.201000548

The first oxoammonium salt mediated formation of C-C bonds from, benzylic C(sp³)-H bonds adjacent to an oxygen or nitrogen, atom by dehydrogenative coupling with enolizable carbonyls has been developed. The use of these oxi- dants in combination with catalytic amounts of Fe(OTf)₂ as Lewis acid, allows the reaction to be carried out under mild conditions, leading to the corresponding coupling products in moderate to good yields.

Full text of DOI:10.1002/ejoc.201000548

FULL PAPER
DOI: 10.1002/ejoc.201000548
Dehydrogenative Functionalization of C(sp3)–H Bonds Adjacent to a
Heteroatom Mediated by Oxoammonium Salts
Heinrich Richter[a] and Olga García Mancheño*[a]
Keywords: C–H activation / Cross-coupling / Dehydrogenation / Iron
The first oxoammonium salt mediated formation of C–C
bonds from benzylic C(sp3)–H bonds adjacent to an oxygen
or nitrogen atom by dehydrogenative coupling with enoliz-
able carbonyls has been developed. The use of these oxi-
dants in combination with catalytic amounts of Fe(OTf)2 as
Lewis acid allows the reaction to be carried out under mild
conditions, leading to the corresponding coupling products
in moderate to good yields.
highly challenging. In particular, the oxidative functionali-
zation of C(sp3)–H bonds adjacent to an oxygen or nitrogen
atom[1,3,4] are of high value in organic synthesis, as func-
tionalized ethers and amines are present in many natural
and bioactive compounds. In this regard, the seminal work
of Li’s group[5] recently expanded the scope of these trans-
formations by using copper, copper/indium, or iron as
metal catalysts (Scheme 1).[1,3e–3g] Iron is a cheap, nontoxic,
and environmentally benign transition metal,[6] thus making
Introduction
In the last few years, cross dehydrogenative coupling (CDC)
reactions have emerged as a powerful and elegant way to
form new C–C bonds from two C–H bonds without requir-
ing preactivation.[1] Although remarkable achievements in
the area of transition-metal-catalyzed selective C–H bond
functionalizations have been made,[2] the direct functionali-
zation of relatively unreactive C(sp3)–H bonds remains
Scheme 1. Strategies for related dehydrogenative functionalizations.
iron-catalyzed C–H functionalizations particularly attract-
ive.[7] On the other hand, in metal-catalyzed CDCs, hydro-
gen acceptors such as organic peroxides, 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ), and dioxygen are employed;
however, the use of potentially explosive peroxides as oxi-
dants is still often required under neat conditions.
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität Münster,
Corrensstraße 40, 48149 Münster, Germany
Fax: +49-251-83-33202
E-mail: olga.garcia@uni-muenster.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000548.
4460
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4460–4467

Dehydrogenative Functionalization of C(sp3)–H Bonds
We focused our attention on 2,2,6,6-tetramethylpiper- Table 1. Optimization of the dehydrogenative coupling of iso-
chromane (1a) with diethylmalonate (2a).[a]
idine-1-oxoammonium salts as a new class of hydrogen ac-
ceptors for dehydrogenative coupling reactions for various
reasons: TEMPO salts (T+Y–) are stable, nontoxic, easily
accessible from readily available nitroxide TEMPO (T·), and
known mild oxidation reagents, generally used for the oxi-
dation of alcohols to the corresponding carbonyl com-
pounds.[8] In addition, these salts are used for the rearrange-
Entry
Catalyst
Y–
Solvent t [h] Yield 3a/4 [%][b]
ment of tertiary allylic alcohols, oxidative additions to ole-
fins, or coupling with enolates, leading to the formation of
C–O bonds.[9] More recently, Bailey and Bobbitt reported
the oxidative cleavage of benzylic ethers through direct C–H
functionalization by using oxoammonium salts as hydrogen
acceptors and water as a nucleophile (Scheme 1).[10]
Although the formation of C–O bonds using TEMPO
derivatives is more likely to occur, we envisioned the forma-
tion of C–C bonds following this dehydrogenative ap-
proach. Thus, a readily formed oxonium or iminium inter-
mediate by dehydrogenation of a C(sp3)–H bond adjacent
to a heteroatom with a TEMPO salt could then react with
an enolate-type nucleophile generated in situ by activation
of a pronucleophile with a Lewis acid metal catalyst to lead
to a new C–C bond (Scheme 1).[11]
–
1
2
3
4
5
6
7
8
FeCl3
FeCl3
FeCl3
FeCl3
–
ClO4
DCM
DCM
DCM
DCM
DCM
DCE
24
24
18
24
24
24
24
24
72
18
18
24
24
24
18
24
24
24
18
55/20
61/11
68/10
–
OTf–
–
BF4
–
BF4–
–
[c,d]
–
FeCl3
FeCl3
FeCl3
FeCl3
FeCl2
FeBr2
Fe(acac)3
BF4–
BF4–
BF4–
BF4–
BF4–
BF4–
BF4–
BF4–
BF4–
BF4
46/nd
[d]
THF
–
MeCN
toluene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
23/nd
63/–[e]
65/–[e]
31/55
9
10
11
12
13
14
15
16
17
18
19
[d]
–
Fe(OTf)3
Fe(OAc)2
Fe(OTf)2
Pd(OAc)2
Cu(OTf)2
CuCl
70/–[e]
50/–[e]
85/–[e]
19/nd
20/nd
–
[f]
–
BF4–
BF4–
BF4–
BF4
Herein we present our recent results on iron-catalyzed
dehydrogenative couplings of benzylic C(sp3)–H bonds ad-
jacent to a heteroatom by using TEMPO oxoammonium
salts (T+Y–) as alternative, mild, safe, and easy-to-handle
oxidizing agents.
CuBr
62/–[e]
[a] Reaction conditions: 1a (0.3 mmol), catalyst (10 mol-%), 2a
(1.2 equiv.) and T+Y– (1.2 equiv.) in the corresponding dry solvent
(0.2 ) at room temperature. [b] Yield after column chromatog-
raphy. [c] Dimer 7 was formed (see mechanistic discussion below).
[d] Trace amounts of 3a detected by GC–MS. [e] Trace amounts of
4 detected by GC–MS. [f] Fe(OTf)3 was prepared in situ from FeCl3
(98%) and AgOTf.
Results and Discussion
The reaction between isochromane (1a) and diethylma-
lonate (2a) was chosen as a model reaction for our study
(Table 1). Initially, various TEMPO salts[12] were tested by Various activated carbon pronucleophiles such as malon-
using inexpensive FeCl3 as the catalyst in CH2Cl2. We were ates and β-keto esters were efficiently utilized in the reac-
pleased to observe the formation of desired coupling prod- tion with isochromane (Table 2, Entries 1–4). Interestingly,
uct 3a in promising yields of 55–68% with the perchlorate, β-nitroketone 2f also worked well (Table 2, Entry 5), thus
triflate, and tetrafluoroborate derivatives (Table 1, En- permitting the introduction of a versatile nitro group that
–
tries 1–3), T+BF4 being the most efficient oxidant (68%; can further be functionalized to the corresponding amine
Table 1, Entry 3).
or carboxylic acid. On the other hand, diketone 2g did not
Moreover, both the iron catalyst and the oxidant were undergo the reaction, probably because of strong coordina-
required to cooperatively activate the pronucleophile and tion to the catalyst (Table 2, Entry 6). The construction of
benzyl ether, respectively (Table 1, Entries 4 and 5). This quaternary carbon atoms was also possible by using α-sub-
reaction was also very dependent on the solvent used. Thus, stituted pronucleophiles, providing the desired products in
other solvents such as DCE, THF, MeCN, and toluene moderate yields (Table 2, Entries 7 and 8). Unfortunately,
hampered or inhibited the reaction (Table 1, Entries 6– further substituents at the benzylic position of isochromane
9).[13] Next, we briefly screened different iron catalysts hampered the reaction, which could be due to the increase
(Table 1, Entries 10–15). Both iron(II) and iron(III) salts in hindrance of the ether (Table 2, Entry 9). Other benzylic
were effective, with the exception of Fe(acac)3. The best re- ethers were then tested (Table 2, Entries 10–13). As ex-
sults were obtained with Fe(OTf)2,[14] which selectively pro- pected, isochromane and its derivatives 1c and 1d were
vided 3a in an excellent yield of 85% (Table 1, Entry 15). found to be more reactive than noncyclic benzyl ethers 1e
Importantly, other transition metals including palladium and 1f. Nevertheless, 1e and 1f were able to react with di-
and copper did not catalyze the reaction as efficiently as ethyl malonate to give 3m and 3n after 16 h in acceptable
iron (Table 1, Entries 16–18), with the exception of com- isolated yields of 46 and 41%, respectively (Table 2, En-
monly used CuBr,[1] which provided 3a in a comparable tries 13 and 14).
62% isolated yield (Table 1, Entry 19).
The reaction with various nitrogenated substrates such
Taking Fe(OTf)2 as the catalyst of choice in combination as N-carbamoyl- or acyl-protected tetrahydroisoquinolines
–
with T+BF4 , we next explored the reaction scope (Table 2). 1g–j were also investigated (Table 2, Entries 14–18). De-
Eur. J. Org. Chem. 2010, 4460–4467
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4461

H. Richter, O. García Mancheño
FULL PAPER
– [a]
Table 2. Scope of the Fe-catalyzed dehydrogenative coupling with the use of T+BF4 .
–
[a] Reaction conditions: 1 (1 equiv.), Fe(OTf)2 (10 mol-%), 2 (1.2 equiv.), T+BF4 (1.2 equiv.) in DCM (0.2 ) at room temperature for 3–
32 h. [b] Yield after column chromatography. [c] Only partial conversion of isochromane was observed and isochromanone 4 was also
formed (isolated yield indicated in brackets). [d] Diastereomeric ratio determined by NMR spectroscopy is given in brackets. [e] The
elimination of MeOH in 3m led to the corresponding conjugated styrene system in 17% yield after 16 h reaction. Prolonged reaction
times provide higher amounts of the elimination product. [f] Benzaldehyde was formed (NMR conversion yield in brackets; see ref.[10a]).
[g] N-Boc benzylamine was formed (yield in brackets). Trace amounts of the C–O coupling product between malonate and TEMPO salt
were also detected by GC–MS (see ref.[9d]).
lightfully, both bulky tert-butyl carbamate (Boc) and piva- sired products 3o–s in good yields after shorter reaction
loyl (Piv) groups at the nitrogen were well tolerated. In ge- times (3–8 h). The intramolecular reactions of N-aryl deriv-
neral, these nitrogenated substrates showed higher reactiv- atives 1k and 1l to give annulated compounds 3t and 3u
ity compared to the oxygenated analogues, leading to de- were also successfully accomplished (Table 2, Entries 19
4462
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4460–4467

Dehydrogenative Functionalization of C(sp3)–H Bonds
and 20). Finally, the reaction of a less reactive acyclic ben- responsible reagent in the key oxidation step. Furthermore,
zylic amine was encouraged. Thus, N,N-diBoc-protected we found that the addition of substoichiometric amounts of
benzylamine 1m led to mono N-Boc-protected derivative 3v TFA (e.g. 0.4 equiv.) to the model reaction was beneficial,
as the major coupling product (30%; Table 2, Entry 21), reducing the reaction time from 18 to 5 h (85 and 80%
along with mono-NBoc benzylamine (50–60%), which does yield, respectively). More interestingly, it was also possible
not react further under the reaction conditions, and the to perform the reaction in the absence of the metal catalyst.
NH2-free compound (Յ10%). This observation is not sur- Although less efficiently, TFA could also promote the reac-
prising because of the acidic reaction media, which can pro- tion of 1a with malonate 2a, leading to coupling product
mote the in situ cleavage of the Boc groups.
3a in a good 60% yield after 24 h.[19] Unfortunately, these
We also carried out preliminary investigations to shed metal-free conditions were not general.[20] Further studies
some light on the reaction mechanism. Two possible mecha- were then carried out for the nitrogenated substrates. Thus,
–
1
nisms, radical and ionic, can be envisioned. However, in the the reaction of 1i with T+BF4 was followed by H NMR
above-mentioned related work recently published by Bob- spectroscopy. A broad signal at 9.2–9.0 ppm appeared,
bitt et al. (Scheme 1),[10] an ionic mechanism involving the which was consistent with the generation of corresponding
formation of an oxonium intermediate by formal hydride iminium ion 5.[21] After 1i was completely consumed
transfer to the oxygen of T+ was proposed (Scheme 1).[15] (Յ16 h), malonate 2a and Fe(OTf)2 were added. Expected
Accordingly, the pronucleophile, activated by the iron cata- coupling product 3r was then formed, although in a low
lyst would react with oxonium or iminium species 5, pre- isolated yield of 20%.
viously generated by dehydrogenation with the TEMPO
salt, to form C–C coupling product 3 (Scheme 2).
Conclusions
In summary, we have developed an efficient method for
the selective construction of C–C bonds by functionaliza-
tion of C(sp3)–H bonds in the α-position to O and N atoms
under mild reaction conditions by using oxoammonium
TEMPO salts as easy-to-handle, nontoxic oxidants. This
methodology provides a safe and easy way to prepare α-
functionalized ethers and amines, such as isochromane and
tetrahydroisoquinoline derivatives, which are key structural
units in natural and biologically active compounds. Mech-
anistic studies suggested that the TEMPO salt is the respon-
sible reagent in the oxidation step, which involves the for-
mation of an oxonium or iminium intermediate, and the Fe
catalyst acts only as a Lewis acid to activate the pronucleo-
Scheme 2. Possible ionic mechanistic pathways.
phile.
On the other hand, the formation of certain amounts of
oxidized product 4 could be explained by the nucleophilic
Experimental Section
attack of trace amounts of water or the in situ formed
TEMPOH[16,17] to the cationic intermediate followed by
oxidation. However, when the reaction of isochromane (1a)
General Information: All reactions were carried out in heat-gun-
dried glassware under an argon atmosphere. Dichloromethane was
distilled from CaH2. 1H, 13C, and 19F NMR spectra were recorded
in CDCl3, chemical shifts (δ) are given in ppm and spin–spin cou-
pling constants (J) are given in Hz. Column chromatography was
performed on silica gel 60 (0.040–0.063 mm). Exact masses
(HRMS) and elemental analyses were recorded with a Bruker Dal-
tonics MicroTof spectrometer and a Vario ELIII, respectively.
Fe(OTf)2 was prepared from iron powder and trifluoromethanesul-
fonic acid as described in the literature.[14b] Isochromanes 1c and
1d[22] and tetrahydroisoquinolines 1g–j[23] and 1m[24] were prepared
following described procedures in the literature. Compound 1k was
prepared by reduction of dimethyl 2-[2-(3,4-dihydroisoquinolin-
2(1H)-yl)benzylidene] malonate[25] and 1l by coupling of ethyl 3-(2-
fluorophenyl)-3-oxopropanoate with tetrahydroisoquinoline.[26]
Commercially available chemicals were used without further purifi-
cation.
–
with T+BF4 was performed in the absence of both malon-
ate and the iron catalyst, oxygenated dimer 7 was
formed.[18] The generation of 7 under the inert and dry con-
ditions employed is still unclear, but could be the result of
the formation of 1-hydroxyisochromane followed by attack
to the oxonium intermediate. Unfortunately, neither 1-hy-
droxyisochromane nor oxonium ion 5 could be isolated.
Considering possible first C–O bond formation followed by
substitution to generate the new C–C bond, new possible
intermediate 7 was then submitted to the reaction with 2a
in the presence of the Fe(OTf)2 catalyst, but no reaction
was observed. Taking into account the original acidic con-
ditions and the known cleavage of dimer 7 with acids,[18a]
TFA (0.4 equiv.) was added after 18 h to the reaction mix-
ture. Then, 7 was cleanly transformed into desired product
3a (77%). This latest finding suggested that the iron species
2,2,6,6-Tetramethylpiperidine-1-oxoammonium Tetrafluoroborate:[9]
In a 25-mL round-bottomed flask, a solution of HBF4 (48% in
acts as a simple Lewis acid, the TEMPO salt being the only H2O, 1.75 mL, 13.1 mmol) was added to a heterogeneous solution
Eur. J. Org. Chem. 2010, 4460–4467
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4463

H. Richter, O. García Mancheño
FULL PAPER
of 2,2,6,6-tetramethylpiperidine-1-oxyl (1.78 g, 11.4 mmol) in dis-
tilled water (6 mL). The reaction mixture was stirred at room tem-
perature for 30 min to give a yellow orange mixture. In an ice bath,
a solution of NaOCl (5% in H2O, 7.8 mL, 5.7 mmol) was added to
the above solution over 1 h. The mixture was filtered, and the yel-
low solid was washed with cooled water (4 °C, 4 ϫ5 mL) and
dichloromethane (3ϫ5 mL). After drying under high vacuum at
50 °C overnight, the product was obtained as a bright yellow solid
(2.2 g, 79%).
Ethyl 2-(Isochroman-1-yl)-3-oxo-3-phenylpropanoate (3e): Follow-
ing the general procedure, 3e was obtained as a mixture of two
diastereoisomers in a 1:1.5 ratio (63%). Chromatography: pentane/
ethyl acetate, 20:1–10:1. 1H NMR (300 MHz, CDCl3): δ = 13.53 (s,
enol, 1 H), 8.02–7.96 (m, 2 H, major), 7.94–7.91 (m, 2 H, minor),
7.59–7.52 (m, 1 H, major; 1 H, minor), 7.48–7.40 (m, 2 H, major;
2 H, minor), 7.23–6.99 (m, 4 H, major; 4 H, minor), 5.78–5.74 (m,
1 H, major; 1 H, minor), 4.94 (d, J = 7.7 Hz, 1 H, major), 4.89 (d,
J = 7.1 Hz, 1 H, minor), 4.25–4.11 (m, 3 H, major; 2 H, minor),
4.07–4.00 (m, 1 H, minor), 3.90–3.81 (m, 1 H, major), 3.76–3.66
(m, 1 H, minor), 3.00–2.84 (m, 1 H, major; 1 H, minor), 2.78 (dt,
J = 16.4, 4.9 Hz, 1 H, major), 2.64 (dt, J = 16.2, 4.2 Hz, 1 H,
minor), 1.16 (t, J = 7.1 Hz, 3 H, major), 1.14 (t, J = 7.1 Hz, 3 H,
minor) ppm. 13C NMR (75 MHz, CDCl3): δ = 193.4, 193.2, 168.2,
167.1, 137.3, 136.6, 135.9, 135.7, 134.5, 134.1, 133.7, 133.3, 129.1,
128.8, 128.7, 128.6, 127.1 (2 C), 126.3, 125.2, 125.0, 74.7, 74.0, 63.4
(2 C), 61.7, 61.6, 61.4, 60.4, 28.8, 28.7, 14.0 (2 C) ppm. HRMS
(ESI+): calcd. for C20H20O4·Na+ 347.1254; found 347.1257.
Preparation of Diethyl 2-(Isochroman-1-yl)malonate (3a) as a Gene-
ral Procedure for the T+BF4 -Mediated Dehydrogenative Coupling:
–
To a mixture of isochromane (1a; 38 µL, 0.30 mmol), diethylmalon-
ate (2a; 55 µL, 0.36 mmol), and Fe(OTf)2 (10.6 mg, 0.03 mmol) in
CH2Cl2 (1.5 mL) at room temperature was added TEMPO+BF4
–
(85 mg, 0.36 mmol). The reaction mixture was stirred until the
starting material was consumed (18 h, monitored by GC–MS and
TLC). The solvent was concentrated under reduced pressure, and
the residue was purified by column chromatography (pentane/ethyl
acetate, 20:1–10:1) to give 3a as a pale-yellow oil (75 mg, 85%). 1H
NMR (300 MHz, CDCl3): δ = 7.21–7.04 (m, 4 H), 5.47 (d, J =
6.3 Hz, 1 H), 4.27–4.09 (m, 5 H), 3.97 (d, J = 6.3 Hz, 1 H), 3.84–
3.75 (m, 1 H), 3.05–2.95 (m, 1 H), 2.71 (dt, J = 16.2, 4.2 Hz, 1 H),
1.23 (t, J = 7.1 Hz, 3 H), 1.14 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.7, 166.9, 135.0, 134.5, 129.1, 127.2,
126.3, 124.8, 74.2, 63.5, 61.8, 61.4, 58.3, 28.7, 14.1, 14.0 ppm.
HRMS (ESI+): calcd. for C16H20O5·Na+ 315.1203; found
315.1198.
2-(Isochroman-1-yl)-2-nitro-1-phenylethanone (3f): Following the
general procedure, 3f was obtained as an inseparable mixture of
two diastereoisomers in a 1:2 ratio (72 mg, 80%). Chromatography:
1
pentane/ethyl acetate, 10:1. H NMR (400 MHz, CDCl3): δ = 7.87
(dd, J = 8.4, 1.2 Hz, 2 H, major), 7.71 (dd, J = 8.4, 1.2 Hz, 2 H,
minor), 7.61 (tt, J = 7.5, 1.2 Hz, 1 H, major), 7.56 (t, J = 7.5 Hz,
1 H, minor), 7.46 (m, 2 H, major), 7.36 (m, 2 H, minor), 7.28–6.98
(m, 4 H, major; 4 H, minor), 6.57 (d, J = 7.2 Hz, 1 H, major), 6.40
(d, J = 5.0 Hz, 1 H, minor), 5.93 (d, J = 5.0 Hz, 1 H, minor), 5.88
(d, J = 7.2 Hz, 1 H, major), 4.23 (dt, J = 11.3, 5.0 Hz, 1 H, major),
4.03 (ddd, J = 11.2, 5.1, 3.1 Hz, 1 H, minor), 3.82 (ddd, J = 11.4,
8.5, 4.1 Hz, 1 H, major), 3.67 (ddd, J = 11.2, 10.1, 3.6 Hz, 1 H,
minor), 3.05–2.97 (m, 1 H, major), 2.78 (dt, J = 16.2, 4.4 Hz, 1 H,
major), 2.67–2.58 (m, 1 H, minor), 2.54 (dt, J = 16.1, 3.2 Hz, 1 H,
minor) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.6, 187.4, 135.3,
135.0, 134.8 (2 C), 134.7, 134.2, 132.7, 131.2, 129.4 (2 C), 129.1,
128.9 (2 C), 128.8, 128.0 (2 C), 127.2, 126.7, 125.5, 124.7, 93.7,
92.7, 74.8, 74.2, 64.1, 63.4, 28.6, 28.5 ppm. HRMS (ESI+): calcd.
for C17H15NO4·Na+ 320.0893; found 320.0883.
Dibenzyl 2-(Isochroman-1-yl)malonate (3b): Following the general
procedure, 3b was obtained as a pale-yellow oil (72%). Chromatog-
1
raphy: pentane/ethyl acetate, 20:1. H NMR (300 MHz, CDCl3): δ
= 7.39–7.26 (m, 8 H), 7.24–7.15 (m, 3 H), 7.14–7.07 (m, 2 H), 7.06–
7.00 (m, 1 H), 5.56 (d, J = 6.0 Hz, 1 H), 5.23 and 5.18 (AB system,
J = 12.3 Hz, 2 H), 5.13 (s, 2 H), 4.21–4.12 (m, 2 H), 3.82–3.72 (m,
1 H), 2.98–2.88 (m, 1 H), 2.68 (dt, J = 16.2, 4.0 Hz, 1 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 167.3, 166.5, 135.4, 135.2, 134.7,
134.4, 129.1, 128.6, 128.4 (2 C), 128.3, 128.2, 127.1, 126.3, 124.6,
74.2, 67.4, 67.1, 63.5, 58.1, 28.6 ppm. HRMS (ESI+): calcd. for
C26H24O5·Na+ 439.1516; found 439.1537.
Dimethyl 2-Chloro-2-(isochroman-1-yl)malonate (3h): Following the
general procedure, 3h was obtained as a white solid (51%).
Chromatography: pentane/ethyl acetate, 10:1. 1H NMR (300 MHz,
CDCl3): δ = 7.28–7.20 (m, 2 H), 7.20–7.12 (m, 2 H), 5.94 (s, 1 H),
4.30–4.20 (m, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.80–3.70 (m, 1 H),
3.20–2.90 (m, 1 H), 2.68 (dt, J = 16.1, 3.9 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.5, 165.3, 136.1, 132.2, 129.0, 127.7,
126.3, 126.0, 78.3, 63.8, 54.3, 54.2, 29.0 ppm. HRMS (ESI+): calcd.
for C14H15ClO5·Na+ 321.0500; found 321.0508.
Dimethyl 2-(Isochroman-1-yl)malonate (3c): Following the general
procedure, 3c was obtained as a pale-yellow oil (40%). Chromatog-
1
raphy: pentane/ethyl acetate, 10:1. H NMR (300 MHz, CDCl3): δ
= 7.22–7.11 (m, 3 H), 7.04–7.01 (m, 1 H), 5.48 (d, J = 6.4 Hz, 1
H), 4.18 (dt, J = 11.3, 4.8 Hz, 1 H), 4.00 (d, J = 6.4 Hz, 1 H), 3.85–
3.75 (m, 1 H), 3.75 (s, 3 H), 3.70 (s, 3 H), 3.05–2.95 (m, 1 H), 2.72
(dt, J = 16.2, 4.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 167.9, 167.1, 134.7, 134.4, 129.1, 127.2, 126.3, 124.6, 74.1,
63.4, 58.1, 52.7, 52.4, 28.6 ppm. HRMS (ESI+): calcd. for
C14H16O5·Na+ 287.0890; found 287.0899.
Ethyl 2-(Isochroman-1-yl)-2-methyl-3-oxobutanoate (3i): Following
the general procedure, 3i was obtained as a mixture of two dia-
stereoisomers in a 1:3.7 ratio (38%). Chromatography: pentane/
1-Benzyl 3-Methyl 2-(Isochroman-1-yl)malonate (3d): Following the ethyl acetate, 10:1. 1H NMR (300 MHz, CDCl3): δ = 7.23–6.95 (m,
general procedure, 3d was obtained as an inseparable mixture of
4 H, major; 4 H, minor), 5.91 (s, 1 H, major), 5.71 (s, 1 H, minor),
two diastereoisomers in a 1:1 ratio (72%). Chromatography: pen-
4.34–4.19 (m, 2 H, major; 2 H, minor), 4.16–4.08 (m, 1 H, major;
tane/ethyl acetate, 10:1. 1H NMR (300 MHz, CDCl3): δ = 7.39– 1 H, minor), 3.68 (td, J = 11.2, 3.1 Hz, 1 H, minor), 3.65 (td, J =
7.27 (m, 8 H), 7.22–6.97 (m, 10 H), 5.51 (d, J = 6.2 Hz, 2 H), 5.24 11.3, 2.9 Hz, 1 H, major), 3.17–2.95 (m, 1 H, major; 1 H, minor),
and 5.17 (AB system, J = 12.3 Hz, 2 H), 5.11 (s, 2 H), 4.20–4.09
(m, 2 H), 4.07 (dd, J = 9.6, 6.2 Hz, 2 H), 3.84–3.72 (m, 2 H), 3.76
(s, 3 H), 3.68 (s, 3 H), 3.03–2.88 (m, 2 H), 2.77–2.62 (m, 2 H) ppm.
2.62–2.50 (m, 1 H, major; 1 H, minor), 2.37 (s, 3 H, major), 2.23
(s, 3 H, minor), 1.29 (t, J = 7.1 Hz, 3 H, major), 1.27 (s, 3 H,
minor), 1.25 (t, J = 7.1·Hz, 3 H, minor), 1.10 (s, 3 H, major) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.0, 167.4, 167.1, 166.6, 135.5, 13C NMR (75 MHz, CDCl3): δ = 205.2, 203.0, 171.2, 135.8, 135.6,
135.3, 134.7, 134.6, 134.4, 129.2, 129.1, 128.6, 128.5 (2 C), 128.4, 134.6, 134.4, 129.3, 126.9, 126.8, 126.4, 126.2, 125.9, 125.3, 78.4,
128.2 (2 C), 127.2 (2 C), 126.4, 126.3, 124.7, 124.5, 74.3, 74.1, 67.4,
77.9, 67.1, 66.6, 64.6, 64.4, 61.9, 61.7, 29.4, 29.3, 27.5, 26.5, 15.2,
67.1, 63.7, 63.4, 58.3, 58.0, 52.8, 52.6, 28.7, 28.6 ppm. HRMS 14.0, 13.3 ppm. HRMS (ESI+): calcd. for C16H20O4·Na+ 299.1254;
(ESI+): calcd. for C20H20O5·Na+ 363.1203; found 363.1212. found 299.1249. C16H20O4 (276.33): calcd. C 69.54, H 7.30; found
C20H20O5 (340.37): calcd. C 70.57, H 5.92; found C 70.26, H 6.04.
4464
C 69.36, H 7.46.
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4460–4467

Dehydrogenative Functionalization of C(sp3)–H Bonds
Diethyl 2-(6-Fluoroisochroman-1-yl)malonate (3k): Following the
general procedure, 3k was obtained as a pale-yellow oil (82%).
Chromatography: pentane/ethyl acetate, 10:1. 1H NMR (300 MHz,
CDCl3): δ = 7.07–7.00 (m, 1 H), 6.86–6.78 (m, 2 H), 5.41 (d, J =
6.2 Hz, 1 H), 4.22–4.10 (m, 5 H), 3.91 (d, J = 6.3 Hz, 1 H), 3.79–
(s, 9 H, minor), 1.30–1.23 (m, 3 H, major; 3 H, minor), 1.14 (t, J
= 7.1 Hz, 3 H, minor), 1.07 (t, J = 7.1 Hz, 3 H, major) ppm. 13C
NMR (100 MHz, CDCl3): δ = 167.6, 167.5, 167.3, 167.2, 154.9,
154.4, 135.4, 134.9, 134.7, 129.0, 128.6, 127.9, 127.7, 127.2, 126.3,
126.2, 80.7, 80.1, 61.7, 61.6, 61.5, 59.5, 59.0, 53.9, 53.2, 40.3, 38.5,
3.71 (m, 1 H), 3.01–2.91 (m, 1 H), 2.64 (dt, J = 16.4, 4.3 Hz, 1 H), 28.4, 28.3, 28.1, 28.0, 14.1, 14.0 (2 C), 13.9 ppm. HRMS (ESI+):
1.21 (t, J = 7.1 Hz, 1 H), 1.15 (t, J = 7.1 Hz, 1 H) ppm. 13C NMR calcd. for C21H29NO6·Na+ 414.1887; found 414.1903.
(75 MHz, CDCl3): δ = 167.5, 166.7, 163.2, 159.9, 136.9, 136.8,
Diethyl 2-[2-(Ethoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-
malonate (3p): Following the general procedure, 3p was obtained
as a pale-yellow oil (80%). Chromatography: pentane/ethyl acetate,
130.7, 130.6, 126.6, 126.5, 115.6, 115.3, 113.5, 113.2, 73.8, 63.0,
61.8, 61.4, 58.2, 28.8 (2 C), 14.0 (2 C) ppm. 19F NMR (282 MHz,
CDCl3):
δ
=
–115.5 ppm. HRMS (ESI+): calcd. for
10:1. This compound exists as a mixture of rotamers in a ratio 1:1.3
C16H19FO5·Na+ 333.1109; found 333.1114. C16H19FO5 (310.32):
1
in CDCl3 at 23 °C. H NMR (300 MHz, CDCl3): δ = 7.31 (d, J =
calcd. C 61.93, H 6.17; found C 61.83, H 6.40.
7.3 Hz, 1 H, minor), 7.25 (d, J = 7.8 Hz, 1 H, major), 7.22–7.15
(m, 1 H, major; 1 H, minor), 7.15–7.08 (m, 2 H, major; 2 H,
minor), 6.01 (d, J = 8.2 Hz, 1 H, minor), 5.94 (d, J = 8.1 Hz, 1 H,
major), 4.25–3.96 (m, 7 H, major; 6 H, minor), 3.87–3.73 (m, 1 H,
major; 2 H, minor), 3.69–3.43 (m, 1 H, minor), 3.53–3-46 (m, 1 H,
major), 3.01–2.81 (m, 2 H, major; 2 H, minor), 1.33–1.17 (m, 6 H,
major, and 6 H, minor), 1.14–1.04 (m, 3 H, major; 3 H,
minor) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.3, 167.0, 155.7,
155.2, 134.6, 134.4, 128.9, 128.5, 127.7, 127.6, 127.2, 126.1, 61.7 (2
C), 61.5, 61.4, 59.0, 58.8, 53.6, 39.7, 38.9, 27.8, 27.5, 14.6, 14.5,
14.0, 13.8 ppm. HRMS (ESI+): calcd. for C19H25NO6·Na+
386.1574; found 386.1583. C19H25NO6 (363.40): calcd. C 62.80, H
6.93, N 3.85; found C 62.43, H 6.95, N 3.86.
Diethyl 2-(4-Methylisochroman-1-yl)malonate (3l): Following the
general procedure, 3l was obtained as a mixture of two diastereo-
isomers in a 1:1.5 ratio (81%). Chromatography: pentane/ethyl
acetate, 20:1–10:1. 1H NMR (300 MHz, CDCl3): δ = 7.26–7.11 (m,
3 H, major; 3 H, minor), 7.07–7.04 (m, 1 H, minor; 1 H, major),
5.51 (d, J = 6.7 Hz, 1 H, major), 5.44 (d, J = 5.7 Hz, 1 H, minor),
4.26–4.10 (m, 5 H, major; 4 H, minor), 4.03 (d, J = 5.7 Hz, 1 H,
minor), 3.97 (d, J = 6.8 Hz, 1 H, major), 3.87 (d, J = 3.8 Hz, 1 H,
major), 3.48 (dd, J = 11.3, 7.2 Hz, 1 H, major), 3.06–2.98 (m, 1 H,
major), 2.86–2.79 (m, 1 H, minor), 1.36 (d, J = 7.1 Hz, 3 H, minor),
1.24 (d, J = 7.0 Hz, 3 H, major), 1.24 (t, J = 7.1 Hz, 3 H, minor)
1.23 (t, J = 7.1 Hz, 3 H, major), 1.16 (t, J = 7.1 Hz, 3 H, minor),
1.14 (t, J = 7.1 Hz, 3 H, major) ppm. 13C NMR (75 MHz, CDCl3):
δ = 167.5, 166.8, 139.6, 139.5, 134.4, 134.3, 128.4, 127.3, 127.2,
126.1, 126.0, 124.6, 124.3, 74.5, 74.3, 69.3, 69.1, 61.7 (2 C), 61.3 (2
C), 58.3, 57.8, 32.5, 31.7, 20.2, 17.8, 14.0, 13.9 (2 C) ppm. HRMS
(ESI+): calcd. for C17H22O5·Na+ 329.1359; found 329.1356.
C17H22O5 (306.35): calcd. C 66.65, H 7.24; found C 66.44, H 7.17.
Ethyl 2-[2-(Ethoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-3-
oxo-3-phenylpropanoate (3q): Following the general procedure, 3q
was obtained as a mixture of two diastereoisomers in a ratio of
1:1.6, which form rotamers, as a pale-yellow oil (83%). Chromatog-
raphy: pentane/ethyl acetate, 5:1. 1H NMR (400 MHz, CDCl3): δ
= 8.04–7.82 (m, 2 H, major; 2 H, minor), 7.63–6.94 (m, 7 H, major;
7 H, minor), 6.44 (d, J = 9.5 Hz, 1 H, minor rotamer of the major
diastereoisomer), 6.37 (d, J = 9.5 Hz, 1 H, major rotamer of the
major diastereoisomer), 6.24 (d, J = 5.5 Hz, 1 H, minor rotamer
of the minor diastereoisomer), 6.17 (d, J = 5.7 Hz, 1 H, major
rotamer of the minor diastereoisomer), 4.89–4.73 (m, 1 H, major,
and 1 H, minor), 4.26–3.39 (m, 6 H, major; 6 H, minor), 3.10–2.80
(m, 2 H, major, and 2 H, minor), 1.33–1.05 (m, 3 H, minor rotamer
of the major diastereoisomer; 3 H, major rotamer of the minor
diastereoisomer; 3 H, minor rotamer of the minor diastereoisomer),
0.92 (t, J = 7.1 Hz, 3 H, major rotamer of the major diastereoiso-
mer) ppm. 13C NMR (100 MHz, CDCl3): δ = 192.7, 192.1, 191.8,
167.9, 167.5, 167.0, 166.5, 155.6, 155.4, 155.2, 136.5, 136.4, 136.0,
135.9, 134.1, 133.9, 133.6, 133.4, 133.1, 129.1, 128.7, 128.6, 128.3,
128.2, 128.0, 127.8, 127.7, 127.5, 127.4, 127.2, 126.2, 126.0, 61.8,
61.7, 61.4, 61.0, 53.6, 53.0, 40.0, 39.6, 39.1, 38.8, 28.1, 27.8, 27.7,
27.3, 14.6, 14.5, 14.3, 13.8, 13.6, 13.5 ppm. HRMS (ESI+): calcd.
for C23H25NO5·Na+ 418.1625; found 418.1629. C23H25NO5
(395.45): calcd. C 69.86, H 6.37, N 3.54; found C 69.57, H 6.37, N
3.63.
Diethyl 2-[Methoxy(phenyl)methyl]malonate (3m): Following the ge-
neral procedure, 3m was obtained as a pale-yellow oil (46%). 1H
NMR (400 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 4.78 (d, J =
10.1 Hz, 1 H), 4.35–4.20 (m, 2 H), 3.92 (qd, J = 7.1, 1.2 Hz, 2 H),
3.74 (d, J = 10.1 Hz, 1 H), 3.19 (s, 3 H), 1.30 (t, J = 7.1 Hz, 3 H),
0.98 (t, J = 10.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
167.4, 166.4, 138.0, 128.7, 128.5, 127.9, 81.9, 61.8, 61.5, 60.1, 57.0,
14.2, 13.8 ppm. HRMS (ESI+): calcd. for C15H20O5·Na+ 303.1203;
found 303.1203.
Diethyl 2-[Isopropoxy(phenyl)methyl]malonate (3n): Following the
general procedure, 3n was obtained as a pale-yellow oil (41%).
Chromatography: pentane/ethyl acetate, 20:1. 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.35 (m, 2 H), 7.33–7.24 (m, 3 H), 4.98 (d, J =
10.2 Hz, 1 H), 4.31–4.18 (m, 2 H), 3.94–3.86 (m, 2 H), 3.70 (d, J
= 10.2 Hz, 1 H), 3.48 (hept., J = 6.1 Hz, 1 H), 1.31 (t, J = 7.1 Hz,
3 H), 1.12 (d, J = 6.1 Hz, 3 H), 0.97 (d, J = 6.1 Hz, 3 H), 0.96 (t,
J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.4,
166.6, 139.7, 128.4, 128.3, 127.9, 77.9, 69.9, 61.6, 61.4, 60.6, 23.4,
21.1, 14.3, 13.8 ppm. HRMS (ESI+): calcd. for C17H24O5·Na+
331.1516; found 331.1522. C17H24O5 (308.37): calcd. C 66.21, H
7.84; found C 66.22, H 7.96.
Diethyl
(3r): Following the general procedure, 3r was obtained as a white
Diethyl 2-[2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-1- solid (69%). Chromatography: pentane/ethyl acetate, 10:1. 1H
2-(2-Pivaloyl-1,2,3,4-tetrahydroisoquinolin-1-yl)malonate
yl]malonate (3o): Following the general procedure, 3o was obtained
as a pale-yellow oil (53%). Chromatography: pentane/ethyl acetate,
10:1. This compound exists as a mixture of rotamers in a ratio 1:1.2
in CDCl3 at 23 °C. 1H NMR (400 MHz, CDCl3): δ = 7.32–7.25 (m,
1 H, major; 1 H, minor), 7.20–7.11 (m, 3 H, major; 3 H, minor),
NMR (300 MHz, CDCl3): δ = 7.33 (d, J = 7.6 Hz, 1 H), 7.20–7.09
(m, 3 H), 6.31 (d, J = 6.6 Hz, 1 H), 4.33–4.23 (m, 1 H), 4.19 (qd,
J = 7.1, 1.2 Hz, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 3.81 (d, J = 6.7 Hz,
1 H), 3.80–3.69 (m, 1 H), 2.93 (ddd, J = 17.3, 11.4, 6.2 Hz), 2.82
(ddd, J = 16.6, 4.2, 2.8 Hz, 1 H), 1.29 (s, 9 H), 1.27 (t, J = 7.1 Hz,
5.99 (d, J = 8.7 Hz, 1 H, minor), 5.91 (d, J = 7.0 Hz, 1 H, major), 3 H), 1.10 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
4.24–3.98 (m, 5 H, major; 4 H, minor), 3.76–3.70 (m, 2 H, minor; δ = 177.2, 167.8, 167.4, 134.7, 133.7, 128.9, 127.6, 127.5, 126.3,
1 H, major), 3.63–3.56 (m, 1 H, minor), 3.47–3.41 (m, 1 H, major), 61.8, 61.6, 59.4, 52.8, 40.6, 39.2, 28.6, 28.5, 14.1, 13.9 ppm. HRMS
2.94–2.82 (m, 2 H, major; 2 H, minor), 1.46 (s, 9 H, major), 1.44 (ESI+): calcd. for C21H29NO5·H+ 376.2118; found 376.2118.
Eur. J. Org. Chem. 2010, 4460–4467
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4465

H. Richter, O. García Mancheño
FULL PAPER
C21H19NO5 (365.38): calcd. C 67.18, H 7.79, N 3.73; found C
67.18, H 7.80, N 3.78.
Acknowledgments
We are grateful for generous support from Prof. Frank Glorius.
Diethyl 2-(2-Acetyl-1,2,3,4-tetrahydroisoquinolin-1-yl)malonate (3s):
Following the general procedure, 3s was obtained as a pale-yellow
oil (72%). Chromatography: pentane/ethyl acetate, 3:1. This com-
pound exists as a mixture of rotamers in a ratio 1:1.8 in CDCl3 at
23 °C. 1H NMR (300 MHz, CDCl3): δ = 7.39–7.34 (m, 1 H, minor),
7.26–7.09 (m, 4 H, major; 3 H, minor), 6.33 (d, J = 7.8 Hz, 1 H,
minor), 5.66 (d, J = 9.5 Hz, 1 H, major), 4.49 (dddd, J = 13.4, 6.7,
4.3, 1.0 Hz, 1 H, major), 4.30–3.97 (m, 4 H, major, and 4 H,
minor), 3.90 (d, J = 9.5 Hz, 1 H, major), 3.86 (m, 1 H, minor),
3.71 (d, J = 7.8 Hz, 1 H, minor), 3.67 (m, 1 H, minor), 3.23 (ddd,
J = 13.6, 9.5, 5.8 Hz, 1 H, major), 3.07–2.78 (m, 2 H, major; 2 H,
minor), 2.26 (s, 3 H, major), 2.11 (s, 3 H, minor), 1.26 (t, J =
7.1 Hz, 3 H, major), 1.26 (t, J = 7.1 Hz, 3 H, minor) 1.17 (t, J =
7.1 Hz, 3 H, major), 1.10 (t, J = 7.1 Hz, 3 H, minor) ppm. 13C
NMR (75 MHz, CDCl3): δ = 170.3, 170.0, 167.4, 167.3 (2 C), 166.7,
134.7 (2 C), 134.5, 134.1, 129.5, 128.4, 128.3, 128.1, 127.8, 126.7,
126.6, 126.3, 62.3, 62.1, 61.8, 61.5, 58.9, 58.6, 56.2, 51.4, 42.1, 36.8,
28.4, 27.3, 22.0, 21.9, 14.1, 14.0 (2 C), 13.9 ppm. HRMS (ESI+):
calcd. for C18H23NO5·Na+ 356.1468; found 356.1467.
[1] For recent reviews on CDCs, see: a) C. J. Li, Acc. Chem. Res.
2009, 42, 335–344; b) C. J. Scheuermann, Chem. Asian J. 2009,
5, 436–451.
[2] G. Dyker (Ed.), Handbook of C–H Transformations, Wiley-
VCH, Weinheim, 2005.
[3] Some representative metal-catalyzed examples: Ir: a) B. De-
Boef, S. J. Pastine, D. Sames, J. Am. Chem. Soc. 2004, 126,
6556–6557; Pd: b) C. Dubs, Y. Hamashima, N. Sasamoto,
T. M. Seidel, S. Suzuki, D. Hashizume, M. Sodeoka, J. Org.
Chem. 2008, 73, 5859–5871; Ru: c) S. J. Pastine, D. V. Gribkov,
D. Sames, J. Am. Chem. Soc. 2006, 128, 14220–14221; d) N.
Chatani, T. Asaumi, S. Yorimitsu, T. Ikeda, F. Kakiuchi, S.
Murai, J. Am. Chem. Soc. 2001, 123, 10935–10941; Cu: e) Z.
Li, D. S. Bohle, C.-J. Li, Proc. Natl. Acad. Sci. USA 2006, 103,
8928–8933; Cu/In: f) Y. Zhang, C.-J. Li, Angew. Chem. Int. Ed.
2006, 45, 1949–1952; g) Y. Zhang, C.-J. Li, Synlett 2009, 138–
142.
[4] For metal-free CDCs, see: a) Y. Zhang, C.-J. Li, J. Am. Chem.
Soc. 2006, 128, 4242–42443; b) Z. Li, H. Li, X. Guo, L. Cao,
R. Yu, H. Li, S. Pan, Org. Lett. 2008, 10, 803–805; c) X.-Z.
Shu, X.-F. Xia, Y.-F. Yang, K.-G. Ji, X.-Y. Liu, Y.-M. Liang,
J. Org. Chem. 2009, 74, 7464–7469; d) A. S. K. Tsang, M. H.
Todd, Tetrahedron Lett. 2009, 50, 1199–1202; e) J. Jin, Y. Li,
Z.-J. Wang, W.-X. Qian, W.-L. Bao, Eur. J. Org. Chem. 2010,
1235–1238.
Diethyl 11b,13-Dihydro-6H-isoquinolino[2,1-a]quinoline-12,12(7H)-
dicarboxylate (3t): Following the general procedure, 3t was ob-
tained as a pale-yellow oil (56%). Chromatography: pentane/DCM,
1:2. 1H NMR (400 MHz, CDCl3): δ = 7.23–7.04 (m, 6 H), 6.78 (d,
J = 8.1 Hz, 1 H), 6.72 (td, J = 7.4, 1.0 Hz, 1 H), 5.09 (s, 1 H), 4.18
(q, J = 7.1 Hz, 2 H), 4.13 (q, J = 7.1 Hz, 1 H), 4.05 (q, J = 7.1 Hz,
1 H), 3.94–3.89 (m, 1 H), 3.63 and 3.48 (AB system, J = 16.4 Hz,
2 H), 3.30 (td, J = 11.6, 3.7 Hz, 1 H), 3.25–3.15 (m, 1 H), 2.75 (dt,
J = 15.5, 3.0 Hz, 1 H), 1.16 (t, J = 7.1 Hz, 1 H), 1.10 (t, J = 7.1 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 169.5, 145.5,
137.0, 135.5, 129.0, 128.7, 127.1, 126.9, 126.2, 125.7, 122.0, 118.3,
112.3, 61.9, 61.6, 61.24, 59.6, 44.2, 33.8, 28.2, 14.0, 13.8 ppm.
HRMS (ESI+): calcd. for C23H25NO4·H+ 380.1862; found
380.1856.
[5] a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2005, 127, 3672–3673; b)
Z. Li, C.-J. Li, Eur. J. Org. Chem. 2005, 3173–3176; c) Z. Li,
C.-J. Li, J. Am. Chem. Soc. 2006, 128, 56–57.
[6] For reviews on iron catalysis, see: a) C. Bolm, J. Legros, J.
Le Paih, L. Zani, Chem. Rev. 2004, 104, 6217–6254; b) A.
Fürstner, R. Martin, Chem. Lett. 2005, 624–629; c) D. D. Diaz,
P. O. Miranda, J. I. Padrón, V. S. Martin, Curr. Org. Chem.
2006, 10, 457–476; d) S. Enthaler, K. Junge, M. Beller, Angew.
Chem. Int. Ed. 2008, 47, 3317–3321; e) B. D. Sherry, A.
Fürstner, Acc. Chem. Res. 2008, 41, 1500–1511; f) E. B. Bauer,
Curr. Org. Chem. 2008, 12, 1341–1369; g) S. Gaillard, J.-L. Re-
naud, ChemSusChem 2008, 1, 505–509; h) A. Correa, O.
García Mancheño, C. Bolm, Chem. Soc. Rev. 2008, 37, 1108–
1117; i) A. Fürstner, Angew. Chem. Int. Ed. 2009, 48, 1364–
1367; j) W. M. Czaplik, M. Mayer, J. Cvengrosˇ, A. J. von Wang-
elin, ChemSusChem 2009, 2, 396–417; see also: B. Plietker
(Ed.), Iron Catalysis in Organic Chemistry: Reactions and Ap-
plications, Wiley-VCH, Weinheim, 2008.
Ethyl 13-Hydroxy-7,11b-dihydro-6H-isoquinolino[2,1-a]quinoline-
12-carboxylate (3u): Following the general procedure, 3u was ob-
tained as a green-yellow oil (68%). Chromatography: pentane/ethyl
acetate, 6:1. 1H NMR (300 MHz, CDCl3): δ = 12.62 (s, 1 H, enol),
7.64 (dd, J = 7.8, 1.6 Hz, 1 H), 7.29–7.33 (m, 1 H), 7.15–7.06 (m,
2 H), 7.04–6.93 (m, 2 H), 6.84 (d, J = 8.3 Hz, 1 H), 6.70 (td, J =
7.8, 0.9 Hz, 1 H), 5.60 (s, 1 H), 4.38 (qq, J = 10.8, 7.1 Hz, 2 H),
4.25–4.15 (m, 2 H), 3.69 (ddd, J = 14.4, 12.3, 5.3 Hz, 1 H), 3.42–
3.30 (m, 1 H), 2.75 (dd, J = 16.9, 5.0 Hz, 1 H), 1.34 (t, J = 7.1 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.9, 165.2, 147.4,
139.3, 134.0, 133.1, 129.1, 126.9, 125.9 (2 C), 125.7, 117.7, 117.6,
112.1, 93.7, 60.9, 55.6, 45.1, 24.2 ppm. HRMS (ESI+): calcd. for
C20H19NO3·Na+ 344.1257; found 344.1264.
[7] For iron-catalyzed C(sp3)–H bond functionalizations, see: a) Y.
Zhang, C.-J. Li, Eur. J. Org. Chem. 2007, 4654–4657; b) Z. Li,
L. Cao, C.-J. Li, Angew. Chem. Int. Ed. 2007, 46, 6505–6507;
c) Z. Li, R. Yu, H. Li, Angew. Chem. Int. Ed. 2008, 47, 7497–
7500; d) Y.-Z. Li, B.-J. Li, X.-Y. Lu, S. Lin, Z.-J. Shi, Angew.
Chem. Int. Ed. 2009, 48, 3817–3820; e) H. Li, Z. He, X. Guo,
W. Li, X. Zhao, Z. Li, Org. Lett. 2009, 11, 4176–4179; f) S.-Y.
Zhang, Y.-Q. Tu, C.-A. Fan, F.-M. Zhang, L. Shi, Angew.
Chem. Int. Ed. 2009, 48, 8761–8765; g) W. Han, A. R. Ofial,
Chem. Commun. 2009, 6023–6025; h) W. Han, A. R. Ofial,
Chem. Commun. 2009, 5024–5026; i) C. M. R. Volla, P. Vogel,
Org. Lett. 2009, 11, 1701–1704; j) H.-P. Bi, W.-W. Chen, Y.-M.
Liang, C.-J. Li, Org. Lett. 2009, 11, 3246–3249; k) X. Guo, S.
Pan, J. Liu, Z. Li, J. Org. Chem. 2009, 74, 8848–8851; l) S. Pan,
J. Liu, H. Li, Z. Wang, X. Guo, Z. Li, Org. Lett. 2010, 12,
1932–1935; for Fe-catalyzed directed arylations, see: m) J. Nor-
inder, A. Matsumoto, N. Yoshikai, E. Nakamura, J. Am. Chem.
Soc. 2008, 130, 5858–5859; n) N. Yoshikai, A. Matsumoto, J.
Norinder, E. Nakamura, Angew. Chem. Int. Ed. 2009, 48, 2925–
2928; o) N. Yoshikai, A. Matsumoto, J. Norinder, E. Naka-
mura, Synlett 2010, 3313–316.
Diethyl 2-[(tert-Butoxycarbonylamino)(phenyl)methyl]malonate (3v):
Following the general procedure, 3u was obtained as a pale-yellow
1
oil (30%). Chromatography: pentane/ethyl acetate, 10:1. H NMR
(300 MHz, CDCl3): δ = 7.35–7.20 (m, 5 H), 6.19 (br. s, 1 H), 5.49
(br. s, 1 H), 4.28–4.02 (m, 4 H), 3.88 (br. d, J = 4.5 Hz, 1 H), 1.40
(s, 9 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.12 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.2, 167.3, 155.2, 139.7, 128.6,
127.7, 126.4, 79.8, 62.1, 61.7, 57.0, 28.4, 14.1, 14.0 ppm. HRMS
(ESI+): calcd. for C19H27NO6·Na+ 388.1731; found 388.1724.
C19H27NO6 (365.42): calcd. C 62.45, H 7.45, N 3.83; found C
62.39, H 7.43, N 3.91.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and copies of
the NMR spectra.
[8] For a comprehensive review on oxoammonium chemistry, see:
a) J. M. Bobbitt, C. Brückner, N. Merbouh, “Oxoammonium-
4466
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4460–4467

Dehydrogenative Functionalization of C(sp3)–H Bonds
and Nitroxide-Catalyzed Oxidations of Alcohols” in Organic
Reactivity (Ed.: S. E. Denmark), Wiley, New York, 2009, vol.
74, pp 103–424; for some recent examples, see: b) W. F. Bailey,
J. M. Bobbitt, K. B. Wiberg, J. Org. Chem. 2007, 72, 4504–
4509; c) C.-X. Miao, L.-N. He, J.-Q. Wang, J.-L. Wanga, Adv.
Synth. Catal. 2009, 351, 2209–2216 and references cited
therein; for oxidations to carboxylic acids, see: d) M. Shibuya,
T. Sato, M. Tomizawa, Y. Iwabuchi, Chem. Commun. 2009,
1739–1741.
[15] When 1.2 equiv. of free–radical scavenger butylated hydroxytol-
uene (BHT) was additional added to the standard T+-mediated
reaction between 1a and 2a, 3a was still formed but in a moder-
ate 40% yield. This result is also consistent with the proposed
ionic mechanism, as phenols can also react with TEMPO salts.
However, a radical pathway cannot be completely ruled out on
the basis of these observations.
[16] Highly unstable TEMPOH was partially oxidized to TEMPO
during manipulation of the GC–MS samples in air.
[17] Trace amounts of 6 (Y = TEMPO) were detected by MS analy-
sis (m/z = 290.4 [M + H]+) from the crude reaction mixture by
using less reactive catalysts such as Pd(OAc)2 (Table 1, En-
try 16).
[18] a) Y.-C. Xu, E. Lebeau, J. W. Gillard, G. Attardo, Tetrahedron
Lett. 1993, 34, 3841–3844; b) M. Eikawa, S. Sakaguchi, Y. Ishii,
J. Org. Chem. 1999, 64, 4676–4679.
[19] The use of other strong organic acids such as TfOH or AcOH
led to undesired products and/or large amounts of isochrom-
anone (4).
[9] See, for example, alcohol rearrangements: a) M. Shibuya, M.
Tomizawa, Y. Iwabuchi, J. Org. Chem. 2008, 73, 4750–4752; b)
M. Shibuya, M. Tomizawa, Y. Iwabuchi, Org. Lett. 2008, 11,
4715–4718; C–O bond formations: c) T. Takata, Y. Tsujino, S.
Nakanishi, K. Nakamura, T. Endo, Chem. Lett. 1999, 9, 937–
938; d) M. Schämann, H. J. Schäfer, Synlett 2004, 1601–1603;
e) P. P. Pradhan, J. M. Bobbitt, W. F. Bailey, Org. Lett. 2006, 8,
5485–5487.
[10] a) P. P. Pradhan, J. M. Bobbitt, W. F. Bailey, J. Org. Chem.
2009, 74, 9524–9527; for a related suggested mechanism involv-
ing prior complexation of the substrate with the oxoammon-
ium salt, see: b) F. Acunzo, P. Baiocco, M. Fabbrini, C. Galli,
P. Gentili, Eur. J. Org. Chem. 2002, 4195–4201.
[11] For precedents on iminium salts and C–C bond formations
with the use of T+Y–, see: J. M. Bobbitt, Z. Ma, Heterocycles
1992, 33, 641–648.
[12] TEMPO salts were prepared by disproportionation of TEMPO
with the corresponding strong acid according to the reported
literature. See ref.[8a]
[20] This metal-free reaction was not efficient for tetrahydroiso-
quinolines, which were not tolerated (1g) or led to complex
mixtures (1j, 19% 3r after 48 h).
[21] For more details on the 1H NMR spectroscopy studies, see the
Supporting Information
[22] D. A. Favor, D. S. Johnson, J. J. Powers, T. Lib, R. Madabattu-
lab, Tetrahedron Lett. 2007, 17, 3039–3041.
[23] a) L. Lemoucheux, J. Rouden, M. Ibazizene, F. Sobrio, M.-C.
Lasne, J. Org. Chem. 2003, 68, 7289–7297; b) M. Berglund,
M. F. Dalence-Guzmán, S. Skogvall, O. Sterner, Bioorg. Med.
Chem. 2008, 16, 2513–2528.
[24] L. Grehn, K. Gunnarsson, U. Ragnarsson, Acta Chem. Scand.,
Ser. B 1986, 40, 745–750.
[25] a) S. Murarka, C. Zhang, M. D. Konieczynska, D. Seidel, Org.
Lett. 2009, 11, 129–132; b) B. C. Ranu, S. Samanta, Tetrahe-
dron 2003, 59, 7901–7906.
[13] In the reaction under neat conditions at 100 °C (see ref.[4a]),
desired coupling product 3a was only formed in small amounts
(10–17%), and 4 was the major isolated product (50–55%).
[14] For the preparation of Fe(OTf)2, see: a) J. S. Haynes, J. R.
Sams, R. C. Thomson, Can. J. Chem. 1981, 59, 669–678; b)
K. S. Hagen, Inorg. Chem. 2000, 39, 5867–5869; for recent ex-
amples on Fe(OTf)2-catalyzed reactions, see: K. L. Klotz,
L. M. Slominski, A. V. Hull, V. M. Gottsacker, R. Mas-Ball-
esté, L. Que Jr., J. A. Halfen, Chem. Commun. 2007, 2063–
2065; c) M. Nakanishi, A.-F. Salit, C. Bolm, Adv. Synth. Catal.
2008, 350, 1835–1840; d) A. Mayer, A.-F. Salit, C. Bolm, Chem.
Commun. 2008, 5975–5977; e) O. García Mancheño, J. Dalli-
more, A. Plant, C. Bolm, Org. Lett. 2009, 11, 2429–2432.
[26] a) D. B. Moran, C. B. Ziegler Jr., T. S. Dunne, N. A. Kuck, Y. I.
Lin, J. Med. Chem. 1989, 32, 1313–1318; b) G. A. Kraus, V.
Gupta, M. Kohut, N. Singh, Bioorg. Med. Chem. Lett. 2009,
19, 5539–5542.
Received: April 20, 2010
Published Online: July 1, 2010
Eur. J. Org. Chem. 2010, 4460–4467
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4467