Carboxylate-assisted ruthenium(II)-catalyzed C-H arylations of 5-aryl tetrazoles: Step-economical access to Valsartan

Article abstract of DOI:10.1016/j.tet.2013.01.006

Carboxylate assistance was key to success for highly efficient ruthenium-catalyzed direct ortho-arylations of tetrazolyl-substituted arenes with aryl halides and triflates in the absence of phosphine ligands. Thus, ruthenium(II) biscarboxylates allowed for C-H bond functionalizations with excellent chemo- and site-selectivities, which set the stage for an atom- and step-economical access to key angiotensin-II-receptor blockers. Mechanistic studies revealed the C-H bond metalation to be reversible, and were suggestive of a rate-determining reductive elimination.

Full text of DOI:10.1016/j.tet.2013.01.006

Tetrahedron xxx (2013) 1e9
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Carboxylate-assisted ruthenium(II)-catalyzed CeH arylations of 5-aryl tetrazoles:
step-economical access to Valsartan
,
Emelyne Diers a, N.Y. Phani Kumar a, Tom Mejuch b, Ilan Marek b, Lutz Ackermann a
*
a Institut fuer Organische und Biomolekulare Chemie, Georg-August Universitaet, Tammannstrasse 2, 37077 Goettingen, Germany
b Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, 32000 Haifa, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
Carboxylate assistance was key to success for highly efficient ruthenium-catalyzed direct ortho-arylations
of tetrazolyl-substituted arenes with aryl halides and triflates in the absence of phosphine ligands. Thus,
ruthenium(II) biscarboxylates allowed for CeH bond functionalizations with excellent chemo- and site-
selectivities, which set the stage for an atom- and step-economical access to key angiotensin-II-receptor
blockers. Mechanistic studies revealed the CeH bond metalation to be reversible, and were suggestive of
a rate-determining reductive elimination.
Received 1 December 2012
Accepted 3 January 2013
Available online xxx
Keywords:
ARB
Arylation
CeH activation
Ruthenium
Valsartan
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
reagents.2 Unfortunately, the prerequisite nucleophiles are not
readily available and their syntheses involve a number of reaction
Hypertension is one of the most prevalent diseases in developed
countries, and nonpeptidic angiotensin-II-receptor blockers (ARBs),
such as Valsartan or Losartan (Fig. 1), have emerged as highly
effective antihypertensives.1 As a consequence, these ARBs are
produced in more than 1000 t per year worldwide for clinical
treatment.
steps, which generate undesired waste. A significantly more atom-
and step-economical approach is represented by the direct aryla-
tion of otherwise unreactive CeH bonds.3,4 Particularly, ruth-
enium(II) complexes have in recent years attracted significant
research interest because of their cost-effective nature as well as
their excellent chemoselectivity and versatility.5 In this context,
Seki very recently reported on a ruthenium-catalyzed direct ary-
6,7
lation approach to ABRs utilizing PPh3 as the liganddyet with
NMP as the solvent, which was recently8 shown to contain impu-
rities that significantly influence the reproducibility of the ruthe-
nium catalyst.9
In 2008, we have introduced carboxylates as cocatalytic addi-
tives for very robust and reliable ruthenium(II)-catalyzed CeH
bond functionalizations.10 Subsequently, preformed or in situ
generated ruthenium(II) biscarboxylates were applied for various
CeH bond activation reactions, and were thereby identified as ar-
guably the most broadly applicable tools for ruthenium-catalyst
direct arylations11,12 and alkylations.11g,13 In consideration of the
particular importance of 5-biaryl-substituted tetrazoles in medici-
nal chemistry, we naturally became attracted by probing our
ruthenium(II) biscarboxylates as the catalysts for direct CeH bond
arylations of 5-aryl tetrazoles. Hence, in contrast to phosphine li-
Fig. 1. Angiotensin-II-receptor blockers bearing 5-biaryl tetrazoles.
5-Biaryl-substituted tetrazoles are the common structural mo-
tifs of numerous nonpeptidic ARBs. Thus far, the biaryl moieties
were mostly constructed through conventional palladium-
catalyzed cross-coupling reactions between electrophilic aryl ha-
lides and nucleophilic organometallic or main group element
gands, we found carboxylates to display
a significant rate-
acceleration in the ruthenium(II)-catalyzed synthesis of 5-biaryl-
substituted tetrazoles,14 which, inter alia, enabled direct arylations
to be performed in apolar solvents and at low catalyst loadings.
* Corresponding author. Tel.: þ49 551 393202; fax: þ49 551 396777; e-mail
addresses: lutz.ackermann@chemie.uni-goettingen.de, lackerm@gwdg.de (L.
Ackermann).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.006
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2
E. Diers et al. / Tetrahedron xxx (2013) 1e9
2. Results and discussion
2.2. Scope and limitations
2.1. Optimization studies
Thereafter, we tested the scope of carboxylate-assisted ruth-
enium(II)-catalyzed direct arylations with MesCO2H as the coca-
talytic additive and K2CO3 as the base (Scheme 1), since this system
gave the highest overall yield of mono- and diarylated products,
and because it had previously proven to be very robust and most
generally applicable. Initially, we set out to unravel the effect of the
N-substituent of the tetrazole directing group in substrates 1be1h.
Interestingly, the tetrazole-substituted arene 1d displaying an
electron-donating ortho-substituent on the benzyl moiety gave
a higher yield of the desired product as compared to the fluoro-
substituted derivative 1e. A comparable observation was made
with para-benzyl-substituted starting materials 1f and 1g. On the
contrary, an N-alkyl-substituted substrate 1h underwent the cata-
lytic CeH bond functionalization with a lower efficacy.
At the outset of our studies, we tested various reaction con-
ditions for the desired ruthenium(II)-catalyzed direct arylation of
5-aryl 1H-tetrazole 1a with aryl bromide 2a (Table 1). With tol-
uene as the solvent, the previously reported ruthenium catalyst9
derived from phosphine PPh3 only provided an unsatisfactory low
yield of biaryl 3aa (entry 1),15 which proved to be comparable to
the one obtained in the absence of any cocatalytic additive (entry
2). On the contrary, significantly improved yields of desired
product 3aa were realized when employing carboxylates as the
cocatalytic additives (entries 3e7). Not surprisingly, the direct
arylation did not occur in the absence of the ruthenium catalyst
(entry 8). Likewise, reactions with H2O as the reaction medium
turned out to be unsuccessful (entry 9), while other organic sol-
vents, including 1,4-dioxane, NMP or DMA, were viable alterna-
tives (entries 10e12). CeH bond functionalizations in the absence
of the stoichiometric base failed to yield the desired product 3aa
(entry 13). Likewise, carbonate bases other than K2CO3 were
found to be considerably less effective (entries 14 and 15). In-
terestingly, the use of KO2CMes as the stoichiometric base com-
pletely inhibited the catalytic reaction (entry 16). As to further
applications it is, however, noteworthy that inexpensive KOAc
proved to be a suitable stoichiometric base for efficient direct
arylations, notably even in the absence of a cocatalytic additive
(entries 17e19). Finally, the complex [RuBr2(p-cymene)]2 was
found to be less effective as compared to its chloro analogue
(entry 20).
Table 1
Optimization of the direct arylation with arene 1aa
Entry
Additive
Base
Solvent
3aa (%)
4aa (%)
1
2
3
4
5
6
7
8
PPh3
d
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
d
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
47
34
52
60
61
64
64
d
d
2
8
10
9
8
Scheme 1. Scope of carboxylate-assisted direct arylations of arenes 1.
KOAc
Given that the simple N-benzyl-substituted tetrazole derivative
1a provided satisfactory results, we subsequently utilized starting
material 1a for exploring the scope with respect to the electrophilic
aryl bromides 2 (Scheme 2). Importantly, our optimized catalytic
system was found to be broadly applicable and displayed a syn-
thetically useful chemoselectivity. Hence, valuable electrophilic
functional groups, including enolizable ketones, or esters, were
well tolerated to furnish the desired products 3aae3af in high
yields. Interestingly, the electron-rich substrate 2g was more effi-
ciently converted than was the 3,5-difluoro-substituted derivative
2h. This reactivity pattern is in agreement with previous findings in
our laboratories,16e18 and is indicative of a rate-determining re-
ductive elimination (vide infra). Generally, substituents in the para-
and meta-positions of the aryl bromides 2 were well tolerated,
while less satisfactory results were obtained with ortho-substituted
electrophiles. Moreover, the catalytic system was not restricted to
aryl bromides 2, but phenol-derived aryl triflates were also found to
be suitable arylating reagents, as illustrated for the synthesis of
products 3aa and 3ai.
t-BuCO2H
1-AdCO2H
KO2CMes
MesCO2H
MesCO2Hb
MesCO2H
MesCO2H
MesCO2H
MesCO2H
KO2CMes
MesCO2H
MesCO2H
d
9
PhMe
H2O
d
d
12
15
19
d
d
8
9
d
10
11
12
13
14
15
16
17
18
19
20
1,4-Dioxanec
NMPd
DMA
45
46
50
d
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Na2CO3
Cs2CO3
KO2CMes
KOAc
KOAc
KOAc
31
41
d
d
d
70
d
2
MesCO2H
KPF6
d
d
7
46
58
MesCO2He
K2CO3
a
General reaction conditions: 1a (0.50 mmol), 2a (0.55 mmol), [RuCl2(p-cym-
ene)]2 (5.0 mol %), additive (10e30 mol %), K2CO3 (1.00 mmol), PhMe (2.0 mL),
120 ꢀC, 18 h; yields of isolated products.
b
Without [RuCl2(p-cymene)]2.
c
100 ꢀC.
140 ꢀC.
Given the importance of heteroarenes in medicinal chemistry,19
we were particularly pleased to find that heteroaryl bromides 2j
d
e
[RuBr2(p-cymene)]2 (5.0 mol %).
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E. Diers et al. / Tetrahedron xxx (2013) 1e9
3
Scheme 4. Direct arylation with ruthenium biscarboxylate 5a.
Scheme 2. Carboxylate-assisted direct arylations with aryl bromides 2.
and 2k were also suitable electrophilic substrates (Scheme 3).
Again, the more electron-rich electrophile 2k provided superior
results.
Scheme 5. Intramolecular competition experiments (Ar¼4-MeC(O)C6H4).
Furthermore, a direct arylation with D2O as the co-solvent
clearly revealed the key ortho-CeH bond metalation on the arene to
be reversible in nature (Scheme 6). Interestingly, the additional H/D
exchange in the ortho-position of the N-benzyl substituent high-
lights the potential for CeH bond activation on benzyl-substituted
tetrazoles. Furthermore, these findings illustrate direct arylations
via six-membered17 ruthenacycles to be significantly more chal-
lenging than transformations through the corresponding five-
membered intermediates.
Scheme 3. Direct CeH functionalization with heteroaryl bromides 2.
2.3. Mechanistic studies
In consideration of the unique efficiency of our carboxylate-
assisted ruthenium(II)-catalyzed direct arylations, we performed
mechanistic studies to rationalize the catalysts mode of action. To
this end, we tested the performance of the well-defined ruth-
enium(II) biscarboxylate complex 5a11f,n,13 in the direct arylation of
arene 1a (Scheme 4). Notably, the isolated complex 5a displayed
a catalytic activity being comparable to the one observed when
using the in situ formed catalytic system (vide supra).
Intramolecular competition experiments with meta-substituted
substrates 1i and 1j showed that steric interactions were largely
governing the site-selectivity of the CeH bond functionalization
process (Scheme 5a, and b). However, substrate 1k bearing a het-
eroatom-substituent in the meta-position delivered significant
amounts of the product 3ka00 via direct arylation at the more con-
gested CeH bond (Scheme 5c)da feature that can be rationalized in
terms of a secondary directing group effect.
Scheme 6. Direct arylation of arene 1a in the presence of D2O.
Based on our mechanistic studies we propose the catalytic cycle
to involve initial reversible cyclometalation through chelation-
assistance (Scheme 7). Thereafter, formal oxidative addition of
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4
E. Diers et al. / Tetrahedron xxx (2013) 1e9
the aryl bromide 2, followed by rate-limiting reductive elimination
furnish the desired product 3, and thereby regenerate the catalyt-
ically active ruthenium(II) complex 4a.
4. Experimental
4.1. General
All catalytic reactions were carried out on a 0.5e1.0 mmol scale
under N2 using pre-dried glassware. Chemicals were obtained from
commercial sources and were used without further purification.
The tetrazoles 1 were prepared according to a literature proce-
dure.9b Toluene was distilled over sodium/benzophenone or was
purified using an M. Braun SPS-800 solvent purification system.
Yields refer to isolated compounds, estimated to be >95% pure by
1H NMR. Chromatography: Merck silica gel 60 (230e400 mesh).
NMR: spectra were recorded on a Varian Unity 300, Varian Mercury
300, or a Varian Inova 500 in the solvent indicated; chemical shifts
(d) are given in parts per million (ppm), coupling constants (J) in
hertz (Hz).
4.2. Representative procedure for ruthenium-catalyzed direct
arylations of tetrazoles: 1-{20-(1-benzyl-1H-tetrazol-5-yl)-
[1,10-biphenyl]-4-yl}ethanone (3aa)and 1,10-{20-(1-benzyl-1H-
tetrazol-5-yl)-[1,10:30,100-terphenyl]-4,400-diyl}diethanone (4aa)
A
suspension of 1a (120 mg, 0.51 mmol), 2a (112 mg,
0.56 mmol), K2CO3 (138 mg, 1.00 mmol), MesCO2H (27.6 mg,
0.17 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (16.1 mg,
0.026 mmol, 5.2 mol %) in dry PhMe (2.0 mL) was stirred for 18 h at
120 ꢀC. Then, H2O (50 mL) was added at ambient temperature. The
aqueous layer was extracted with CH2Cl2 (35ꢁ0 mL), the combined
organic layers were washed with brine (50 mL), dried over Na2SO4,
and concentrated in vacuo. The remaining residue was purified by
column chromatography on silica gel (n-hexane/EtOAc 2:1) to yield
3aa (116 mg, 64%) as white solids and 4aa (21 mg, 9%) as a white
solid. Compound 3aa. Mp: 157e159 ꢀC. 1H NMR (300 MHz, CDCl3):
Scheme 7. Proposed catalytic cycle.
2.4. Synthesis of the key ARB intermediate
Given the significant interest in atom- and step-economical
syntheses of antihypertensive ARBs, we became attracted by fur-
ther testing the direct arylation of arene 1d with para-substituted
aryl bromide 2c (Scheme 8). Notably, the carboxylate-assisted ru-
thenium-catalyzed CeH bond functionalization occurred very
efficientlydeven with significantly reduced catalyst loadings.
d
¼7.87e7.78 (m, 2H), 7.67 (td, J¼7.7, 1.4 Hz, 1H), 7.57 (dd, J¼7.7,
1.4 Hz, 1H), 7.49 (td, J¼7.7, 1.4 Hz, 1H), 7.37 (dd, J¼7.7, 1.4 Hz, 1H),
7.24e7.09 (m, 5H), 6.85e6.69 (m, 2H), 4.88 (s, 2H), 2.58 (s, 3H). 13
NMR (75 MHz, CDCl3):
¼197.4 (Cq), 154.2 (Cq), 143.3 (Cq), 140.7
C
d
(Cq), 136.3 (Cq), 132.8 (Cq), 131.7 (CH), 131.2 (CH), 130.3 (CH), 128.9
(CH),128.8 (CH),128.7 (CH),128.7 (CH),128.5 (CH),127.7 (CH),122.7
(Cq), 51.0 (CH2), 26.6 (CH3). IR (ATR): 1680, 1496, 1437, 1402, 1357,
1265, 959, 849, 721, 700 cmꢂ1. MS (EI) m/z (relative intensity): 354
(12), 353 (35), 325 (10), 206 (8), 192 (8), 179 (8), 164 (11), 151 (6), 91
(100), 65 (15), 43 (38). HRMS (EI) m/z calcd for C22H18N4Oþ [Mþ]
354.1481, found 354.1468.
Compound 4aa. Mp: 220e223 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼7.83e7.64 (m, 5H), 7.54 (d, J¼7.7 Hz, 2H), 7.24 (ddt, J¼7.8, 7.4,
1.4 Hz, 1H), 7.14 (t, J¼7.4 Hz, 2H), 7.07e6.96 (m, 4H), 6.69 (dd, 7.1,
1.6 Hz, 2H), 4.72 (s, 2H), 2.55 (s, 6H). 13C NMR (75 MHz, CDCl3):
d
¼197.4 (Cq), 152.3 (Cq), 143.2 (Cq), 142.5 (Cq), 136.2 (Cq), 132.3 (Cq),
131.5 (Cq), 129.9 (CH), 129.2 (CH), 128.9 (CH), 128.3 (CH), 128.1 (CH),
121.2 (Cq), 50.9 (CH2), 26.6 (CH3). IR (ATR): 1683, 1604, 1424, 1394,
1354, 1264, 1111, 962, 825, 803, 726, 702, 596 cmꢂ1. MS (EI) m/z
(relative intensity): 473 (12), 472 (37), 471 (35), 283 (12), 239 (19þ),
91 (100), 65 (10), 43 (74). HRMS (EI) m/z calcd for C30H24N4O2
[Mþ] 472.1899, found 472.1902.
Scheme 8. Preparation of the key ARB precursor 3dc.
3. Conclusions
In summary, we have disclosed the significant rate-acceleration
exerted by carboxylates in ruthenium(II)-catalyzed direct aryla-
tions of arenes bearing tetrazoles as the site-selectivity ensuring
directing groups. Thus, in situ generated as well as well-defined
ruthenium(II) biscarboxylate complexes enabled highly efficient
direct arylations of 5-aryl tetrazoles with excellent chemo- and
site-selectivity as well as ample scope. The optimized catalytic
system was utilized for the preparation of the key angiotensin-II-
receptor blocker intermediate with low catalyst loadings. Mecha-
nistic studies were indicative of a reversible CeH bond metalation
and a rate-limiting reductive elimination.
4.3. 1-[20-(1-Benzyl-1H-tetrazol-5-yl)-50-methoxy-(1,10-bi-
phenyl)-4-yl]ethanone (3ba)
Following the general procedure, 1b (136 mg, 0.51 mmol), 2a
(109 mg, 0.60 mmol), K2CO3 (139 mg,1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3ba (108 mg, 57%) was obtained as a green solid after pu-
rification by column chromatography on silica gel (n-hexane/EtOAc
5:1). Mp: 153e154 ꢀC. 1H NMR (300 MHz, CDCl3)
d
¼7.80
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E. Diers et al. / Tetrahedron xxx (2013) 1e9
5
(d, J¼8.3 Hz, 2H), 7.29 (d, J¼8.5 Hz, 1H), 7.24e7.09 (m, 5H), 7.05 (d,
J¼2.6 Hz, 1H), 6.99 (dd, J¼8.5, 2.6 Hz, 1H), 6.79 (d, 2H), 4.87 (s, 2H),
d
¼197.3 (Cq), 160.0 (Cq, JCeF¼249 Hz), 154.4 (Cq), 143.3 (Cq), 140.7
(Cq), 136.3 (Cq), 131.7 (CH), 131.2 (CH), 130.7 (CH, JCeF¼8Hz), 130.2
(CH), 129.8 (CH, JCeF¼3 Hz), 128.9 (CH), 128.8 (CH), 128.5(CH), 124.4
(CH, JCeF¼4 Hz), 122.5 (Cq), 120.2 (Cq, JCeF¼14 Hz), 115.5 (CH,
JCeF¼21 Hz), 44.4 (CH2, JCeF¼5 Hz), 26.6 (CH3). 19F NMR (282 MHz,
3.90 (s, 3H), 2.56 (s, 3H). 13C NMR (75 MHz, CDCl3)
d¼197.3 (Cq),
161.8 (Cq), 154.1 (Cq), 143.3 (Cq), 142.2 (Cq), 136.2 (Cq), 132.9 (Cq),
132.6 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH), 127.6
(CH), 115.9 (CH), 114.4 (Cq), 113.8 (CH), 55.6 (CH3), 50.7 (CH2), 26.6
(CH3). IR (ATR): 1677, 1601, 1467, 1444, 1268, 1221, 848 cmꢂ1. HRMS
(ESI) m/z calcd for C23H20N4O2 [MþHþ] 385.1659, found 385.1658.
CDCl3)
d
¼ꢂ(117.9e118.0) (m). IR (ATR): 1680, 1602, 1493, 1468,
1450, 1264, 1240, 799, 766 cmꢂ1. HRMS (ESI) m/z calcd for
C
22H17N4OF [MþHþ] 373.1459, found 373.1454.
4.4. 1-[20-(1-Benzyl-1H-tetrazol-5-yl)-50-methyl-(1,10-biphenyl)-
4.7. 1-(20-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)-[1,10-bi-
4-yl]ethanone (3ca)
phenyl]-4-yl)ethanone (3fa)
Following the general procedure, 1c (127 mg, 0.50 mmol), 2a
(109 mg, 0.55 mmol), K2CO3 (139 mg,1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3ca (104 mg, 56%) was obtained as a white solid after pu-
rification by column chromatography on silica gel (n-hexane/EtOAc
Following the general procedure, 1f (136 mg, 0.51 mmol), 2a
(109 mg, 0.55 mmol), K2CO3 (139 mg,1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2 mL) for 18 h at 120 ꢀC. Com-
pound 3fa (121 mg, 62%) was obtained as a white solid after puri-
fication by column chromatography on silica gel (n-hexane/EtOAc
5:1). Mp: 149e151 ꢀC. 1H NMR (300 MHz, CDCl3)
d
¼7.82 (d,
5:1). Mp: 117e119 ꢀC. 1H NMR (300 MHz, CDCl3)
d
¼7.84e7.77 (m,
J¼8.6 Hz, 2H), 7.36 (dt, J¼1.5, 0.8, 0.8 Hz, 1H), 7.32e7.06 (m, 7H),
2H), 7.67 (td, J¼7.6, 1.4 Hz, 1H), 7.58 (dd, J¼7.8, 1.4 Hz, 1H), 7.50 (td,
J¼7.5, 1.4 Hz, 1H), 7.36 (dd, J¼7.7, 1.4 Hz, 1H), 7.21e7.12 (m, 2H),
6.68e6.61 (m, 4H), 4.81 (s, 2H), 3.72 (s, 3H), 2.57 (s, 3H). 13C NMR
6.80e6.74 (m, 2H), 4.85 (s, 2H), 2.56 (s, 3H), 2.48 (s, 3H). 13C NMR
(125 MHz, CDCl3)
d
¼197.4 (Cq), 154.3 (Cq), 143.6 (Cq), 142.0 (Cq),
140.6 (Cq), 136.2 (Cq), 132.9 (Cq), 131.1 (CH), 130.1 (CH), 129.3 (CH),
128.9 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 127.7 (CH), 119.7 (Cq),
50.8 (CH2), 26.6 (CH3), 21.5 (CH3). IR (ATR): 1675, 1601, 1495, 1453,
1268, 1229, 833 cmꢂ1. HRMS (ESI) m/z calcd for C23H20N4O [MþHþ]
369.1710; found 369.1708.
(75 MHz, CDCl3)
d
¼197.4 (Cq), 159.7 (Cq), 153.9 (Cq), 143.3 (Cq), 140.7
(Cq), 136.2 (Cq), 131.6 (CH), 131.2 (CH), 130.2 (CH), 129.2 (CH), 128.9
(CH), 128.8 (CH), 128.7 (CH), 128.5 (CH), 124.8 (Cq), 122.8 (Cq), 114.0
(CH), 55.2 (CH3), 50.5 (CH2), 26.6 (CH3). IR (ATR): 1677, 1513, 1400,
1326, 1244, 1179, 1100, 1034, 775 cmꢂ1. HRMS (EI) m/z calcd for
C
23H20N4O2 [MþHþ] 385.1659, found 385.1657.
4.5. 1-(20-(1-(2-Methoxybenzyl)-1H-tetrazol-5-yl))-([1,10-bi-
phenyl]-4-yl)ethanone (3da)
4.8. 1-(20-(1-(4-Fluorobenzyl)-1H-tetrazol-5-yl)-[1,10-bi-
phenyl]-4-yl)ethanone (3ga)
Following the general procedure, 1d (268 mg, 1.00 mmol), 2a
(217 mg, 1.10 mmol), K2CO3 (278 mg, 2.00 mmol), MesCO2H
(53.1 mg, 0.32 mmol, 32 mol %), and [RuCl2(p-cymene)]2 (31.4 mg,
0.05 mmol, 5.0 mol %) were stirred in PhMe (3.0 mL) for 18 h at
120 ꢀC. Compound 3da (250 mg, 65%) was obtained as a light yel-
low solid after purification by column chromatography on silica gel
(n-hexane/EtOAc 4:1/2:1). Mp: 112e114 ꢀC. 1H NMR (300 MHz,
Following the general procedure, 1g (127 mg, 0.50 mmol), 2a
(109 mg, 0.55 mmol), K2CO3 (139 mg,1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3ga (74 mg, 40%) was obtained as a white solid after puri-
fication by column chromatography on silica gel (n-hexane/EtOAc
CDCl3):
d
¼7.89e7.77 (m, 2H), 7.66 (ddd, J¼7.8, 7.1, 1.6 Hz, 1H), 7.57
5:1). Mp: 156e157 ꢀC. 1H NMR (300 MHz, CDCl3)
d
¼7.88e7.78 (m,
(ddd, J¼7.7, 1.4, 0.6 Hz, 1H), 7.51 (td, J¼7.4, 1.4 Hz, 1H), 7.45 (ddd,
J¼7.8, 1.6, 0.6 Hz, 1H), 7.24e7.15 (m, 3H), 6.80 (dd, J¼7.5, 2.0 Hz, 1H),
6.74 (td, J¼7.4, 1.0 Hz, 1H), 6.69 (dd, J¼8.4, 1.0 Hz, 1H), 4.80 (s, 2H),
2H), 7.68 (td, J¼7.6, 1.4 Hz, 1H), 7.58 (ddd, J¼7.8, 1.4, 0.6 Hz, 1H), 7.50
(td, J¼7.5, 1.4 Hz, 1H), 7.36 (ddd, J¼7.7, 1.4, 0.6 Hz, 1H), 7.24e7.13 (m,
2H), 6.91e6.67 (m, 4H), 4.82 (s, 2H), 2.57 (s, 3H). 13C NMR (125 MHz,
3.51 (s, 3H), 2.58 (s, 3H). 13C NMR (125 MHz, CDCl3):
d¼197.4 (Cq),
CDCl3)
d
¼197.3 (Cq), 162.6 (Cq, JCeF¼249 Hz), 154.1 (Cq), 143.2 (Cq),
156.6 (Cq), 154.3 (Cq), 143.6 (Cq), 140.8 (Cq), 136.1 (Cq), 131.3 (CH),
131.3 (CH), 130.1 (CH), 130.1 (CH), 129.8 (CH), 128.9 (CH), 128.6 (CH),
128.2 (CH), 123.2 (Cq), 121.2 (Cq), 120.5 (CH), 110.3 (CH), 55.0 (CH3),
46.0 (CH2), 26.6 (CH3). IR (ATR): 1686, 1603, 1495, 1402, 1251, 1018,
844, 772, 760, 599 cmꢂ1. MS (EI) m/z (relative intensity): 384 (24),
383 (25), 356 (8), 235 (10), 207 (32), 206 (35), 179 (15), 164 (15), 121
140.6 (Cq), 136.3 (Cq), 131.8 (CH), 131.2 (CH), 130.3 (CH), 129.6 (CH,
JCeF¼8 Hz), 128.9 (CH), 128.8 (CH), 128.7 (CH), 128.6 (Cq, JCeF¼3 Hz),
122.6 (Cq), 115.8 (CH, JCeF¼22 Hz), 50.2 (CH2), 26.6 (CH3). 19F NMR
(282 MHz, CDCl3):
d¼ꢂ(112.2e112.4) (m). IR (ATR): 1679, 1601,
1469, 1453, 1402, 1263, 1221, 958, 768 cmꢂ1. HRMS (ESI) m/z calcd
for C22H17N4OF [MþHþ] 373.1459, found 373.1454.
þ
(100), 91 (70). HRMS (EI) m/z calcd for C23H19N4O2 [MꢂHþ]
383.1508, found 383.1510.
4.9. 1-{20-(n-Butyl-1H-tetrazol-5-yl)-[1,10-biphenyl]-4-yl}
ethanone (3ha)
4.6. 1-(20-(1-(2-Fluorobenzyl)-1H-tetrazol-5-yl)-[1,10-bi-
phenyl]-4-yl)ethanone (3ea)
Following the general procedure, 1h (102 mg, 0.50 mmol), 2a
(111 mg, 0.55 mmol), K2CO3 (143 mg, 1.03 mmol), MesCO2H
(26.9 mg, 0.16 mmol, 32 mol %), and [RuCl2(p-cymene)]2 (15.8 mg,
0.026 mmol, 5.2 mol %) were stirred in PhMe (2.0 mL) for 18h at
120 ꢀC. Compound 3ha (85 mg, 53%) was obtained as a colorless oil
after purification by column chromatography on silica gel (n-hex-
Following the general procedure, 1e (130 mg, 0.51 mmol), 2a
(109 mg, 0.55 mmol), K2CO3 (139 mg,1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3ea (100 mg, 53%) was obtained as a colorless solid after
purification by column chromatography on silica gel (n-hexane/
EtOAc 5:1). Mp: 103e105 ꢀC. 1H NMR (300 MHz, CDCl3)
ane/EtOAc 3:1). 1H NMR (300 MHz, CDCl3):
d¼7.91e7.84 (m, 2H),
7.74e7.65 (m, 1H), 7.62e7.55 (m, 3H), 7.23 (d, J¼7.5 Hz, 2H), 3.55
(dd, J¼8.1, 6.8 Hz, 2H), 2.57 (s, 3H), 1.43e1.29 (m, 2H), 1.10e0.91 (m,
d
¼7.88e7.80 (m, 2H), 7.68 (ddd, J¼8.0, 7.0, 1.0 Hz, 1H), 7.58 (ddd,
2H), 0.69 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3):
¼197.3 (Cq),
d
J¼8.0, 1.0, 1.0 Hz, 1H), 7.51 (td, J¼7.0, 1.0 Hz, 1H), 7.42 (dd, J¼8.0,
1.0 Hz, 1H), 7.25e7.19 (m, 3H), 6.99e6.85 (m, 2H), 6.80 (td, J¼7.0,
2.0 Hz, 1H), 4.87 (s, 2H), 2.58 (s, 3H). 13C NMR (125 MHz, CDCl3)
154.2 (Cq), 143.5 (Cq), 140.5 (Cq), 136.3 (Cq), 131.7 (CH), 131.5 (CH),
130.3 (CH), 128.9 (CH), 128.8 (CH), 128.6 (CH), 122.9 (Cq), 47.0 (CH2),
30.6 (CH2), 26.6 (CH3), 19.4 (CH2), 13.1 (CH3). IR (film): 2960, 1681,
Please cite this article in press as: Diers, E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.01.006

6
E. Diers et al. / Tetrahedron xxx (2013) 1e9
1604, 1438, 1357, 1262, 1005, 841, 763, 596 cmꢂ1. MS (EI) m/z (rel-
ative intensity): 319 (100) [MꢂHþ], 291 (45), 263 (8), 249 (18), 178
(14), 151 (10), 43 (30). HRMS (ESI) m/z calcd for C19H19N4Oþ
[MꢂHþ] 319.1559, found 319.1564.
367 (85), 339 (32), 206 (15), 192 (25), 178 (17), 164 (21), 151 (12), 91
(100), 65 (15). HRMS (ESI) m/z calcd for C23H19N4Oþ [MꢂHþ]
367.1559, found 367.1557.
4.13. 20-(1-Benzyl-1H-tetrazol-5-yl)-[1,10-biphenyl]-4-yl(phenyl)
methanone (3ae)
4.10. 1-Benzyl-5-(40-methyl-[1, 10-biphenyl]-2-yl)-1H-tetrazole
(3ab)
Following the general procedure, 1a (119 mg, 0.50 mmol), 2e
(149 mg, 0.57 mmol), K2CO3 (138 mg, 1.00 mmol), MesCO2H
(24.6 mg, 0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (16.4 mg,
0.026 mmol, 5.2 mol %) were stirred in PhMe (2.0 mL) for 18 h at
120 ꢀC. 3ae (174 mg, 70%) was obtained as a white solid after pu-
rification by column chromatography on silica gel (n-hexane/EtOAc
Following the general procedure, 1a (118 mg, 0.50 mmol), 2b
(97 mg, 0.57 mmol), K2CO3 (139 mg, 1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3ab (82 mg, 50%) was obtained as a colorless solid after
purification by column chromatography on silica gel (n-hexane/
EtOAc 6:1). Mp: 143e144 ꢀC. 1H NMR (300 MHz, CDCl3)
5:1). Mp: 123e126 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼7.79e7.65 (m,
5H), 7.66e7.56 (m, 2H), 7.54e7.45 (m, 3H), 7.38 (dd, J¼7.8, 1.4 Hz,
d
¼7.67e7.52 (m, 2H), 7.45e7.30 (m, 2H), 7.23e7.06 (m, 5H),
7.06e7.00 (m, 2H), 6.81e6.64 (m, 2H), 4.77 (s, 2H), 2.34 (s, 3H). 13
NMR (75 MHz, CDCl3)
1H), 7.25e7.12 (m, 5H), 6.80 (dt, J¼6.5, 1.6 Hz, 2H), 4.93 (s, 2H). 13
C
C
NMR (125 MHz, CDCl3):
d
¼195.8 (Cq), 154.2 (Cq), 142.7 (Cq), 140.8
d
¼154.7 (Cq), 141.6 (Cq), 138.0 (Cq), 135.9 (Cq),
(Cq), 137.2 (Cq), 136.8 (Cq), 132.8 (Cq), 132.6 (CH), 131.6 (CH), 131.2
(CH), 130.5 (CH), 130.4 (CH), 129.9 (CH), 128.8 (CH), 128.7 (CH),
128.4 (CH), 126.6 (CH), 128.5 (CH), 128.3 (CH), 122.7 (Cq), 51.0 (CH2).
IR (ATR): 1653, 1600, 1446, 1402, 1276, 1098, 923, 794, 767, 697, 664,
633 cmꢂ1. MS (EI) m/z (relative intensity): 416 (55) [M], 415 (100),
387 (26), 269 (8), 164 (8), 105 (30), 91 (60), 77 (22), 65 (10). HRMS
(ESI) m/z calcd for C27H21N4Oþ [MþHþ] 417.1715, found 417.1710.
133.1 (Cq), 131.5 (CH), 131.2 (CH), 130.1 (CH), 129.7 (CH), 128.6 (CH),
128.5 (CH), 128.4 (CH), 127.8 (CH), 127.5 (CH), 122.6 (Cq), 50.8 (CH2),
21.1 (CH3). IR (ATR): 1597, 1495, 1470, 1457, 1240, 1074, 756 cmꢂ1
.
HRMS (ESI) m/z calcd for C21H18N4 [MþHþ] 327.1604; found
327.1604.
4.11. (20-(1-Benzyl-1H-tetrazol-5-yl)-[1,10-biphenyl]-4-yl)methyl
acetate (3ac)
4.14. tert-Butyl 20-(1-benzyl-1H-tetrazol-5-yl)-[1,10-biphenyl]-
4-yl-carboxylate (3af)
Following the general procedure, 1a (119 mg, 0.50 mmol), 2c
(134 mg, 0.58 mmol), K2CO3 (139 mg, 1.00 mmol), MesCO2H
(30.2 mg, 0.18 mmol, 36 mol %), and [RuCl2(p-cymene)]2 (16.8 mg,
0.027 mmol, 5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at
120 ꢀC. Compound 3ac (114 mg, 59%) was obtained as a white solid
after purification by column chromatography on silica gel (n-hex-
Following the general procedure, 1a (120 mg, 0.51 mmol), 2f
(169 mg, 0.65 mmol), K2CO3 (140 mg, 1.00 mmol), MesCO2H
(24.6 mg, 0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15.6 mg,
0.025 mmol, 5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at
120 ꢀC. Compound 3af (121 mg, 58%) was obtained as a white solid
after purification by column chromatography on silica gel (n-hex-
ane/EtOAc 6:1) and recrystallization from EtOAc. Mp: 190e192 ꢀC.
ane/EtOAc 5:1). Mp: 72e73 ꢀC. 1H NMR (300 MHz, CDCl3):
d¼7.64
(dddd, J¼7.8, 7.1, 1.4, 0.7 Hz, 1H), 7.55 (ddd, J¼7.8, 1.4, 0.7 Hz, 1H),
7.44 (tdd, J¼7.3, 1.4, 0.7 Hz, 1H), 7.34 (dt, J¼8.4, 0.7 Hz, 1H),
7.29e7.23 (m, 2H), 7.21e7.09 (m, 5H), 6.78e6.72 (m, 2H), 5.08 (s,
1H NMR (300 MHz, CDCl3):
d
¼7.88 (dd, J¼7.1, 3.0 Hz, 2H), 7.66 (td,
J¼7.6, 1.5 Hz, 1H), 7.58 (dd, J¼7.6, 1.5 Hz, 1H), 7.47 (td, J¼7.5, 1.5 Hz,
1H), 7.36 (dd, J¼7.7, 1.3 Hz, 1H), 7.25e7.10 (m, 5H), 6.76 (dt, J¼6.9,
1.5 Hz, 2H), 4.83 (s, 2H), 1.59 (s, 9H). 13C NMR (125 MHz, CDCl3):
2H), 4.82 (s, 2H), 2.13 (s, 3H). 13C NMR (125 MHz, CDCl3):
d
¼170.7
(Cq), 154.5 (Cq), 141.2 (Cq), 138.6 (Cq), 135.9 (Cq), 133.0 (Cq), 131.6
(CH),131.2 (CH),130.3 (CH), 128.8 (CH), 128.7 (CH), 128.5 (CH),128.5
(CH), 127.9 (CH), 127.7 (CH), 122.6 (Cq), 65.5 (CH2), 50.8 (CH2), 20.9
(CH3). IR (ATR): 1724,1498,1469,1248,1108, 971, 926, 834, 824, 740,
716, 700, 666, 560, 528 cmꢂ1. MS (EI) m/z (relative intensity): 384
(50) [M], 383 (100), 355 (17), 251 (20), 205 (20), 192 (8), 178 (20),
177 (28), 165 (12), 151þ(10), 91 (86), 65 (14), 43 (21). HRMS (EI) m/z
calcd for C23H19N4O2 [MꢂHþ] 383.1508, found 383.1503.
d¼165.0 (Cq), 154.3 (Cq), 142.7 (Cq), 140.9 (Cq), 132.9 (Cq), 131.6 (CH),
131.5 (Cq), 131.2 (CH), 130.2 (CH), 129.9 (CH), 128.7 (CH), 128.6 (CH),
128.5 (CH), 128.3 (CH), 127.6 (CH), 122.7 (Cq), 81.4 (Cq), 50.9 (CH2),
28.1 (CH3). IR (ATR): 1699, 1470, 1457, 1438, 1401, 1363, 1295, 1161,
1121, 1106, 861, 848, 721, 556, 535 cmꢂ1. MS (EI) m/z (relative in-
tensity): 412 (55), 411 (100), 355 (57), 339 (15), 327 (19), 209 (13),
164 (15), 91 (86), 57 (31). HRMS (ESI) m/z calcd for C25H25N4O2þ
[MþHþ] 413.1978, found 413.1972.
4.12. 1-(20-(1-Benzyl-1H-tetrazol-5-yl)-[1,10-biphenyl]-4-yl)
propan-1-one (3ad)
4.15. 1-Benzyl-5-(30,40,50-trimethoxy-[1,10-biphenyl]-2-yl)-1H-
tetrazole (3ag)
Following the general procedure, 1a (122 mg, 0.51 mmol), 2d
(126 mg, 0.58 mmol), K2CO3 (139 mg, 1.00 mmol), MesCO2H
(25.6 mg, 0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15.4 mg,
0.025 mmol, 5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at
120 ꢀC. Compound 3ad (119 mg, 63%) was obtained as a white solid
after purification by column chromatography on silica gel (n-hex-
Following the general procedure, 1a (118 mg, 0.50 mmol), 2g
(136 mg, 0.60 mmol), K2CO3 (139 mg,1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3ag (140 mg, 69%) was obtained as a colorless liquid after
purification by column chromatography on silica gel (n-hexane/
ane/EtOAc 5:1). Mp: 90e91 ꢀC. 1H NMR (300 MHz, CDCl3):
d¼7.85
(dt, J¼8.5, 1.5 Hz, 2H), 7.67 (ddd, J¼8.8, 7.8, 1.2 Hz, 1H), 7.58 (ddd,
J¼7.8, 1.3, 0.5 Hz, 1H), 7.49 (td, J¼7.5, 1.4 Hz, 1H), 7.37 (ddd, J¼7.8,
1.3 Hz, 1H), 7.23e7.10 (m, 5H), 6.77 (d, J¼6.6 Hz, 2H), 4.86 (s, 2H),
2.97 (q, J¼7.2 Hz, 2H), 1.23 (t, J¼7.2 Hz, 3H). 13C NMR (125 MHz,
EtOAc 4:1). 1H NMR (300 MHz, CDCl3)
d
¼7.67e7.57 (m, 2H), 7.42
(ddd, J¼7.8, 6.1, 2.5 Hz, 1H), 7.36e7.31 (m, 1H), 7.24e7.09 (m, 3H),
6.81e6.72 (m, 2H), 6.34 (s, 2H), 4.84 (s, 2H), 3.83 (s, 3H), 3.67 (s, 6H).
13C NMR (75 MHz, CDCl3)
d
¼154.8 (Cq), 153.3 (Cq), 141.4 (Cq), 137.8
CDCl3):
d
¼200.0 (Cq), 154.2 (Cq), 143.1 (Cq), 140.7 (Cq), 136.1 (Cq),
(Cq), 133.1 (Cq), 132.9 (Cq), 131.6 (CH), 131.2 (CH), 129.8 (CH), 128.6
(CH), 128.5 (CH), 127.7 (CH), 127.6 (CH), 122.5 (Cq), 105.7 (CH), 60.9
(CH3), 56.1 (CH3), 50.7 (CH2). IR (film): 1584, 1568, 1508, 1470, 1455,
1240,1122,1001, 763. HRMS (ESI) m/z calcd for C23H22N4O3 [MþHþ]
403.1765, found 403.1766.
132.8 (Cq), 131.6 (CH), 131.1 (CH), 130.2 (CH), 128.8 (CH), 128.7 (CH),
128.6 (CH), 128.4 (CH), 128.4 (CH), 127.6 (CH), 122.7 (Cq), 50.9 (CH2),
31.8 (CH2), 8.0 (CH3). IR (ATR): 1682, 1400, 1223, 953, 804, 772, 759,
718, 705, 584 cmꢂ1. MS (EI) m/z (relative intensity): 368 (30) [M],
Please cite this article in press as: Diers, E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.01.006

E. Diers et al. / Tetrahedron xxx (2013) 1e9
7
4.16. 1-Benzyl-5-(30,50-difluoro-[1,10-biphenyl]-2-yl)-1H-tetra-
zole (3ah)
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3ak (101 mg, 63%) was obtained as a white solid after pu-
rification by column chromatography on silica gel (n-hexane/EtOAc
Following the general procedure, 1a (118 mg, 0.50 mmol), 2h
(110 mg, 0.57 mmol), K2CO3 (139 mg, 1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3ah (78 mg, 45%) was obtained as a colorless liquid after
purification by column chromatography on silica gel (n-hexane/
6:1). Mp: 90e92 ꢀC. 1H NMR (300 MHz, CDCl3)
d
¼7.65 (dd, J¼8.0,
1.0 Hz, 1H), 7.59e7.53 (m, 1H), 7.39e7.08 (m, 6H), 6.90 (dd, J¼5.1,
3.6 Hz, 1H), 6.84e6.76 (m, 2H), 6.59 (dd, J¼3.6, 1.2 Hz, 1H), 4.90 (s,
2H). 13C NMR (75 MHz, CDCl3)
d
¼154.2 (Cq), 140.1 (Cq), 134.4 (Cq),
132.9 (Cq), 131.5 (CH), 131.4 (CH), 130.0 (CH), 128.7 (CH), 128.5 (CH),
128.2 (CH), 127.9 (CH), 127.8 (CH), 127.0 (CH), 126.9 (CH), 122.2 (Cq),
50.9 (CH2). IR (ATR): 1494, 1470, 1457, 1240, 1159, 1098, 1074,
756 cmꢂ1. MS (EI) m/z (relative intensity): 318 ([Mþ] 28), 317 (53),
289 (30), 91 (100). HRMS (EI) m/z calcd for C18H14N4S [MꢂHþ]
317.0861; found 317.0872.
EtOAc 5:1). 1H NMR (300 MHz, CDCl3)
d
¼7.64 (td, J¼7.5, 1.4 Hz, 1H),
7.54e7.40 (m, 2H), 7.33 (dd, J¼8.0, 1.4 Hz, 1H), 7.27e7.10 (m, 3H),
6.85e6.73 (m, 2H), 6.66 (tt, J¼8.8, 2.3 Hz, 1H), 6.58e6.40 (m, 2H),
5.04 (s, 2H). 13C NMR (125 MHz, CDCl3)
d¼162.7 (Cq, JCeF¼250,
13 Hz), 153.8 (Cq), 141.8(Cq, JCeF¼9 Hz), 139.8 (Cq, JCeF¼2 Hz), 132.8
(Cq), 131.6 (CH), 130.1 (CH), 130.2 (CH), 128.8 (CH), 128.7 (CH),
128.6 (CH), 127.6 (CH), 122.7 (Cq), 111.71 (CH, JCeF¼20, 7 Hz), 103.4
(CH, JCeF¼25 Hz), 50.1 (CH2). 19F NMR (282 MHz, CDCl3)
4.20. 1-{20-(1-Benzyl-1H-tetrazol-5-yl)-40-methyl-[1,10-bi-
phenyl]-4-yl}ethanone (3ia)
d
¼ꢂ(108.16e108.33) (m). IR (film): 1622, 1593, 1497, 1406, 1099,
Following the general procedure, 1i (126 mg, 0.50 mmol), 2a
(113 mg, 0.57 mmol), K2CO3 (139 mg, 1.00 mmol), MesCO2H
(28.2 mg, 0.17 mmol, 34 mol %), and [RuCl2(p-cymene)]2 (16.4 mg,
0.026 mmol, 5.2 mol %) were stirred in PhMe (2.0 mL) for 18 h at
120 ꢀC. Compound 3ia (121 mg, 65%) was obtained as a yellow solid
after purification by column chromatography on silica gel (n-hex-
987, 860, 689 cmꢂ1. MS (EI) m/z (relative intensity): 348 ([Mþ] 38),
347 (48), 319 (32), 201 (48), 91 (100). HRMS (EI) m/z calcd for
C
20H14N4F2 [MꢂH] 347.1108; found 347.1116.
4.17. 1-[20-(1-Benzyl-1H-tetrazol-5-yl)-(1,10-biphenyl)-3-yl]
ethanone (3ai)
ane/EtOAc 3:1). Mp: 126e129 ꢀC. 1H NMR (600 MHz, CDCl3):
d¼7.79
(ddd, J¼8.3, 2.0, 1.6 Hz, 2H), 7.44 (s, 1H), 7.44 (s, 1H), 7.18 (tdd, J¼7.4,
Following the general procedure, 1a (118 mg, 0.50 mmol), 2i
(109 mg, 0.55 mmol), K2CO3 (139 mg,1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3ai (117 mg, 66%) was obtained as a colorless liquid after
purification by column chromatography on silica gel (n-hexane/
2.0,1.3 Hz,1H), 7.16e7.10 (m, 5H), 6.74 (d, J¼7.2 Hz, 2H), 4.83 (s, 2H),
2.54 (s, 3H), 2.36 (s, 3H). 13C NMR (75 MHz, CDCl3):
d¼197.4 (Cq),
154.4 (Cq), 143.4 (Cq), 138.7 (Cq), 137.7 (Cq), 136.0 (Cq), 132.9 (Cq),
132.4 (CH),131.7 (CH), 130.1 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH),
128.5 (CH), 127.7 (CH), 122.4 (Cq), 50.9 (CH2), 26.6 (CH3), 20.9 (CH3).
IR (ATR): 2918, 1682, 1603, 1405, 1237, 1205, 1072, 955, 830, 717,
702, 601 cmꢂ1. MS (EI) m/z (relative intensity): 368 (30), 367 (77),
339 (22), 221 (8), 178 (17), 91 (100), 65 (10), 43 (27). MS (EI) m/z
calcd for C23H19N4Oþ [MꢂHþ] 367.1559, found 367.1560.
EtOAc 5:1). 1H NMR (300 MHz, CDCl3)
d
¼7.85 (d, J¼7.6 Hz, 1H), 7.76
(s, 1H), 7.66 (dd, J¼7.5, 1.5 Hz, 1H), 7.59 (d, J¼7.9 Hz, 1H), 7.48 (td,
J¼7.5, 1.4 Hz, 1H), 7.40e7.05 (m, 6H), 6.76 (d, J¼6.8 Hz, 2H), 4.87 (s,
2H), 2.49 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
¼197.4 (Cq), 154.3 (Cq),
140.8 (Cq), 139.1 (Cq), 137.4 (Cq), 133.1 (CH), 132.8 (Cq), 131.9 (CH),
131.1 (CH), 130.3 (CH), 129.1 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH),
128.2 (CH), 127.7 (CH), 127.6 (CH), 122.6 (Cq), 50.9 (CH2), 26.6 (CH3).
IR (ATR): 1682, 1405, 1357, 1227, 1100, 758 cmꢂ1. MS (EI) m/z (rel-
ative intensity): 354 ([Mþ] 28), 353 (41), 326 (21), 325 (68), 91
(100). HRMS (EI) m/z calcd for C22H18N4O [MꢂHþ] 353.1402, found
353.1411.
4.21. 1-[4-{30-(100-Benzyl-1H-tetrazol-5-yl)naphthalen-2-yl}
phenyl]ethanone (3ja)
Following the general procedure, 1j (144 mg, 0.50 mmol), 2a
(111 mg, 0.56 mmol), K2CO3 (141 mg, 1.02 mmol), MesCO2H
(25.4 mg, 0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (16.5 mg,
0.026 mmol, 5.2 mol %) were stirred in PhMe (2.0 mL) for 18 h at
120 ꢀC. Compound 3ja (96.8 mg, 48%) was obtained as a white solid
after purification by column chromatography on silica gel (n-hex-
4.18. 3-[2-(1-Benzyl-1H-tetrazol-5-yl)phenyl]pyridine (3aj)
ane/EtOAc 4:1). Mp: 175e177 ꢀC. 1H NMR (300 MHz, CDCl3):
d¼8.02
Following the general procedure, 1a (118 mg, 0.50 mmol), 2j
(98 mg, 0.62 mmol), K2CO3 (139 mg, 1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at 120 ꢀC. Com-
pound 3aj (46 mg, 30%) was obtained as a green liquid after puri-
fication by column chromatography on silica gel (n-hexane/EtOAc
(s, 1H), 7.96 (dd, J¼8.2, 1.3 Hz, 1H), 7.90 (s, 1H), 7.84 (dd, J¼8.5,
1.9 Hz, 3H), 7.69e7.56 (m, 2H), 7.25 (dd, J¼8.6, 1.9 Hz, 2H), 7.19e7.03
(m, 3H), 6.76 (dd, J¼6.8, 1.6 Hz, 2H), 4.92 (s, 2H), 2.57 (s, 3H). 13C
NMR (125 MHz, CDCl3):
d¼197.2 (Cq), 154.2 (Cq), 143.4 (Cq), 136.8
(Cq), 136.0 (Cq), 134.1 (Cq), 132.8 (Cq), 131.9 (Cq), 131.9 (CH), 129.7
(CH),129.0 (CH),128.6 (CH),128.6 (CH),128.5 (CH),128.5 (CH),128.1
(CH), 128.0 (CH), 127.6 (CH), 127.6 (CH), 120.3 (Cq), 51.0 (CH2), 26.7
(CH3). IR (ATR): 1675, 1597, 1492, 1430, 1356, 1264, 1118, 1099, 956,
836, 735, 603, 476 cmꢂ1. MS (EI) m/z (relative intensity): 404 (38),
403 (70), 375 (15), 257 (10), 227 (10), 214 (20), 91 (100), 65 (10), 43
(20). HRMS (EI) m/z calcd for C26H19N4Oþ [MꢂHþ] 403.1559, found
403.1575.
5:1). 1H NMR (300 MHz, CDCl3)
d
¼8.49 (d, J¼4.6 Hz, 1H), 8.39 (s,
1H), 7.67 (t, J¼7.6 Hz, 1H), 7.59e7.44 (m, 2H), 7.40e7.04 (m, 6H),
6.78 (d, J¼7.0 Hz, 2H), 4.97 (s, 2H).13C NMR (125 MHz, CDCl3)
d
¼153.7 (Cq), 148.9 (CH), 148.8 (CH), 138.3 (Cq), 135.8 (CH), 134.3
(Cq), 132.6 (Cq), 131.6 (CH), 130.8 (CH), 130.3 (CH), 128.6 (CH), 128.5
(CH), 128.4 (CH), 127.5 (CH), 122.8 (CH), 122.7 (Cq), 50.9 (CH2). IR
(film): 1603, 1404, 1274, 1247, 1026, 791, 761. HRMS (ESI) m/z calcd
for C19H15N5 [MþHþ] 314.1400, found 314.1399.
4.22. 1-(20-(1-Benzyl-1H-tetrazol-5-yl)-40-methoxy-[1,10-bi-
phenyl]-4-yl)ethanone (3ka0) and 1-(20-(1-benzyl-1H-tetrazol-
5-yl)-60-methoxy-[1,10-biphenyl]-4-yl)ethanone (3ka00)
4.19. 1-Benzyl-5-{2-(thiophen-2-yl)phenyl}-1H-tetrazole
(3ak)
Following the general procedure, 1k (136 mg, 0.51 mmol), 2a
(114 mg, 0.57 mmol), K2CO3 (141 mg, 1.02 mmol), MesCO2H
(25.7 mg, 0.16 mmol, 32 mol %), and [RuCl2(p-cymene)]2 (15.8 mg,
0.026 mmol, 5.2 mol %) were stirred in PhMe (2.0 mL) for 18 h at
Following the general procedure, 1a (118 mg, 0.50 mmol), 2k
(99 mg, 0.60 mmol), K2CO3 (139 mg, 1.00 mmol), MesCO2H (25 mg,
0.15 mmol, 30 mol %), and [RuCl2(p-cymene)]2 (15 mg, 0.025 mmol,
Please cite this article in press as: Diers, E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.01.006

8
E. Diers et al. / Tetrahedron xxx (2013) 1e9
120 ꢀC. Compounds 3ka0 (67.6 mg, 35%) and 3ka00 (22.8 mg, 12%)
were obtained as a yellow solid and a white solid after purification
by column chromatography on silica gel (n-hexane/EtOAc
5:1/4:1/3:1).
agreement no. 307535 is gratefully acknowledged. We also thank
Dr. D.S. Yufit (University of Durham) for an X-ray diffraction
analysis.
Compound 3ka0. Mp: 128e130 ꢀC. 1H NMR (300 MHz, CDCl3):
Supplementary data
d
¼7.81 (dt, J¼8.1, 2.5 Hz, 2H), 7.49 (d, J¼8.7 Hz, 1H), 7.22e7.10 (m,
6H), 6.81 (d, J¼2.7 Hz, 1H), 6.77 (dt, J¼6.8, 1.5 Hz, 2H), 4.84 (s, 2H),
3.77 (s, 3H), 2.56 (s, 3H). 13C NMR (125 MHz, CDCl3):
¼197.1 (Cq),
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.01.006.
d
159.3 (Cq), 154.1 (Cq), 143.1 (Cq), 135.8 (Cq), 132.8 (Cq), 132.8 (Cq),
131.5 (CH), 128.7 (CH), 128.6 (CH), 128.6 (CH), 128.5 (CH), 127.6 (CH),
123.6 (Cq), 118.0 (CH), 115.7 (CH), 55.6 (CH3), 51.0 (CH2), 26.6 (CH3).
IR (ATR): 1669,1603,1513,1401,1269,1230,1029, 850, 823, 731, 721,
706, 646, 599 cmꢂ1. MS (EI) m/z (relative intensity): 384 (25), 383
(65), 355 (20), 236 (10), 151 (12), 91 (100), 65 (14), 43 (19). MS (EI)
m/z calcd C23H19N4Oþ [MꢂHþ] 383.1508, found 383.1518.
References and notes
1. Selected contributions: (a) Kim, J. H.; Lee, J. H.; Paik, S. H.; Kim, J. H.; Chi, Y. H.
Arch. Pharm. Res. 2012, 35, 1123e1126; (b) de Catarina, A. R.; Harper, A. R.;
Cuculi, F. Vasc. Health Risk Manag. 2012, 8, 299e305 and references cited
therein; (c) Buhlmayer, P.; Furet, P.; Criscione, L.; de Gasparo, M.; Whitebread,
S.; Schmidlin, T.; Lattmann, R.; Wood, J. Bioorg. Med. Chem. Lett. 1994, 4, 29e34;
(d) Chang, L. L.; Ashton, W. T.; Flanagan, K. L.; Chen, T.-B.; O’Malley, S. S.;
Zingaro, G. J.; Kivlighn, S. D.; Siegl, P. K. S.; Lotti, V. J.; Chang, R. S. L.; Greenlee,
W. J. J. Med. Chem. 1995, 38, 3741e3758; (e) Duncia, J. V.; Chiu, A. T.; Carini, D. J.;
Gregory, G. B.; Johnson, A. L.; Price, W. A.; Wells, G. J.; Wong, P. C.; Calabrese, J.
C.; Timmermans, P. M. W. M. J. Med. Chem. 1990, 33, 1312e1329.
2. Representative recent Valsartan syntheses: (a) Wang, G.; Sun, B.; Peng, C. Org.
Process Res. Dev. 2011, 15, 986e988; (b) Aalla, S.; Gilla, G.; Bojja, Y.; Anumula, R.
R.; Vummenthala, P. R.; Padi, P. R. Org. Process Res. Dev. 2012, 16, 682e686; (c)
Senthil, K.; Reddy, S. B.; Sinha, B. K.; Mukkanti, D.; Dandala, R. Org. Process Res.
Dev. 2009, 13, 1185e1189; (d) Beutler, U.; Boehm, M.; Fuenfschilling, P. C.; Heinz,
T.; Mutz, J.-P.; Onken, U.; Mueller, M.; Zaugg, W. Org. Process Res. Dev. 2007, 11,
892e898; (e) Ghosh, S.; Kumar, A. S.; Mehta, G. N. Beilstein J. Org. Chem. 2010, 6,
27; (f) Goossen, L. J.; Melzer, B. J. Org. Chem. 2007, 72, 7473e7476.
Compound 3ka00. Mp: 59e60 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼7.80 (dt, J¼8.5, 2.0 Hz, 2H), 7.46 (t, J¼7.7 Hz, 1H), 7.25e7.17 (m,
4H), 7.15 (dd, J¼8.5, 1.9 Hz, 2H), 6.95 (dd, J¼7.7, 0.9 Hz, 1H), 6.86 (dt,
J¼6.4, 1.3 Hz, 2H), 4.96 (s, 2H), 3.83 (s, 3H), 2.57 (s, 3H). 13C NMR
(125 MHz, CDCl3):
d
¼197.5 (Cq), 156.9 (Cq), 153.8 (Cq), 139.3 (Cq),
136.0 (Cq), 133.1 (Cq), 130.5 (CH), 129.9 (Cq), 129.7 (CH), 128.8 (CH),
128.7 (CH), 127.9 (CH), 127.8 (CH), 124.7 (Cq), 122.7 (CH), 113.8 (CH),
56.0 (CH3), 50.9 (CH2), 26.5 (CH3). IR (ATR): 2931, 1679, 1606, 1498,
1435, 1401, 1260, 1080, 1024, 751, 721, 698, 602 cmꢂ1. MS (EI) m/z
(relative intensity): 384 (30), 383 (60), 355 (15), 237 (11), 194 (13),
165 (8), 151 (8), 91 (100), 65 (13), 43 (15). HRMS (ESI) m/z calcd for
3. Ackermann, L. Modern Arylation Methods; Wiley-VCH: Weinheim, Germany,
2009.
þ
C
23H21N4O2 [MþHþ] 385.1665, found 385.1659.
4. Representative recent reviews: (a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res.
2012, 45, 936e946; (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem.
Res. 2012, 45, 788e802; (c) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902e4911; (d)
Wencel-Delord, J.; Droege, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40,
4740e4761; (e) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8,
4503e4513; (f) Daugulis, O. Top. Curr. Chem. 2010, 292, 57e84; (g) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624e655; (h) Satoh, T.; Miura,
M. Chem.dEur. J. 2010, 16, 11212e11222; (i) Ackermann, L.; Vicente, R.; Kapdi, A.
Angew. Chem., Int. Ed. 2009, 48, 9792e9826 and references cited therein.
5. Recent reviews: (a) Kozhushkov, S. I.; Potukuchi, H. K.; Ackermann, L. Catal. Sci.
Technol. 2013, http://dx.doi.org/10.1039/C2CY20505J; (b) Kozhushkov, S I.;
4.23. Direct arylation with D2O as the co-solvent
Following the general procedure, 1a (121 mg, 0.51 mmol), 2a
(137 mg, 0.55 mmol), K2CO3 (139 mg, 1.00 mmol), MesCO2H
(25.1 mg, 0.18 mmol, 36 mol %), and [RuCl2(p-cymene)]2 (16.5 mg,
0.027 mmol, 5.4 mol %) were stirred in a solvent mixture of PhMe
and D2O (1.8/0.2 mL) for 18 h at 120 ꢀC. [D]n-3ag (152 mg, 74%) was
obtained as a colorless oil after purification by column chroma-
tography on silica gel (n-hexane/EtOAc 3:1). The D-incorporation in
[D]n-3ag was estimated by 1H NMR spectroscopy.
Ackermann, L. Chem. Sci. 2013,
, http://dx.doi.org/10.1039/C2SC21524A; (c)
Arockiam, P B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879e5918; (d)
Ackermann, L. Isr. J. Chem. 2010, 50, 652e663; (e) Ackermann, L. Pure Appl.
Chem. 2010, 82, 1403e1413; (f) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010,
292, 211e229; (g) Ackermann, L. Chem. Commun. 2010, 4866e4877.
6. For ruthenium-catalyzed direct arylations with PPh3 as the ligand in NMP as
the solvent: (a) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y.
Org. Lett. 2001, 3, 2579e2581; (b) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org.
Chem. 2005, 70, 3113e3119.
4.24. 1-((20-(1-(2-Methoxybenzyl)-1H-tetrazol-5-yl)-[1,10-bi-
phenyl]-4-yl)oxy))propan-2-one) (3dc)9b
Following the general procedure, 1d (134 mg, 0.50 mmol), 2c
(126 mg, 0.55 mmol), K2CO3 (140 mg, 1.01 mmol), MesCO2H
(26.7 mg, 0.16 mmol, 32 mol %), and [RuCl2(p-cymene)]2 (15.4 mg,
0.025 mmol, 5.0 mol %) were stirred in PhMe (2.0 mL) for 18 h at
120 ꢀC. Compound 3dc (156 mg, 75%) was obtained as a white solid
after purification by column chromatography on silica gel (n-hex-
7. For illustrative related examples, see: (a) Lakshman, M. K.; Deb, A. C.; Chamala,
R. R.; Pradhan, P.; Pratap, R. Angew. Chem., Int. Ed. 2011, 50, 11400e11404; (b)
Doherty, S.; Knight, J. G.; Addyman, C. R.; Smyth, C. H.; Ward, N. A. B.;
Harrington, R. W. Organometallics 2011, 30, 6010e6016; (c) Yu, B.; Yan, X.;
Wang, S.; Tang, N.; Xi, C. Organometallics 2010, 29, 3222e3226; (d) Miura, H.;
Wada, K.; Hosokawa, S.; Inoue, M. Chem.dEur. J. 2010, 16, 4186e4189; (e)
Ackermann, L.; Born, R.; Vicente, R. ChemSusChem 2009, 546e549; (f)
Ackermann, L.; Althammer, A.; Born, R. Tetrahedron 2008, 64, 6115e6124; (g)
Ackermann, L.; Althammer, A.; Born, R. Synlett 2007, 2833e2836; (h)
Ackermann, L.; Born, R.; Alvarez-Bercedo, P. Angew. Chem., Int. Ed. 2007, 46,
6364e6367; (i) Ackermann, L. Org. Lett. 2005, 7, 3123e3125.
8. Ouellet, S. G.; Roy, A.; Molinaro, C.; Angelaud, R.; Marcoux, J.-F.; O’Shea, P. D.;
Davies, I. W. J. Org. Chem. 2011, 76, 1436e1439.
ane/EtOAc 4:1). Mp: 119e121 ꢀC. 1H NMR (300 MHz, CDCl3):
d¼7.64
ꢀ
(ddd, J¼8.0, 6.5, 2.1 Hz, 1H), 7.55 (ddd, J¼7.7, 1.3, 0.7 Hz, 1H),
7.51e7.40 (m, 2H), 7.30e7.24 (m, 2H), 7.20 (ddd, J¼8.5, 6.9, 2.3 Hz,
1H), 7.13 (d, J¼7.9 Hz, 2H), 6.83e6.72 (m, 2H), 6.69 (d, J¼8.3 Hz, 1H),
5.08 (s, 2H), 4.75 (s, 2H), 3.51 (s, 3H), 2.13 (s, 3H). 13C NMR
9. (a) Seki, M. ACS Catal. 2011, 1, 607e610; (b) Seki, M.; Nagahama, M. J. Org. Chem.
2011, 76, 10198e10206; (c) Seki, M. Synthesis 2012, 3231e3237.
(125 MHz, CDCl3):
d
¼170.8 (Cq), 156.7 (Cq), 154.6 (Cq), 141.4 (Cq),
10. Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10, 2299e2302.
11. For selected subsequent examples of carboxylate-assisted ruthenium-catalyzed
CeH bond functionalizations from our laboratories, see: (a) Ackermann, L.;
139.0 (Cq), 135.7 (Cq), 131.3 (CH), 131.2 (CH), 130.1 (CH), 130.1 (CH),
130.0 (CH), 128.8 (CH), 128.4 (CH), 127.7 (CH), 123.2 (Cq), 121.5 (Cq),
120.5 (CH), 110.3 (CH), 65.6 (CH2), 55.0 (CH3), 46.1 (CH2), 21.0 (CH3).
IR (ATR): 1733, 1538, 1495, 1278, 1099, 923, 838, 521 cmꢂ1. HRMS
ꢀ
Mulzer, M. Org. Lett. 2008, 10, 5043e5045; (b) Ackermann, L.; Novak, P. Org. Lett.
2009, 11, 4966e4969; (c) Ackermann, L.; Vicente, R. Org. Lett. 2009, 11,
ꢀ
4922e4925; (d) Ackermann, L.; Jeyachandran, R.; Potukuchi, H. K.; Novak, P.;
þ
(ESI) m/z calcd for C24H23N4O3 [MþHþ] 415.1770, found 415.1765.
€
Buttner, L. Org. Lett. 2010, 12, 2056e2059; (e) Ackermann, L.; Vicente, R.; Po-
tukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032e5035; (f) Ackermann, L.;
ꢀ
Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi, H. K. Synthesis 2010, 2245e2253;
Acknowledgements
(g) Ackermann, L.; Hofmann, N.; Vicente, R. Org. Lett. 2011, 13, 1875e1877; (h)
Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50,
6379e6382; (i) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153e4155; (j)
Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548e6551; (k) Ackermann, L.;
Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177e180; (l) Ackermann, L.; Pospech, J.;
Graczyk, K.; Rauch, K. Org. Lett. 2012, 14, 930e933; (m) Ackermann, L.; Pospech,
J.; Potukuchi, H. K. Org. Lett. 2012, 14, 2146e2149; (n) Graczyk, K.; Ma, W.;
Support by the CaSuS PhD program, the DAAD (fellowship to
NYPK), the Niedersachsen-Technion Research Cooperation Program
and the European Research Council under the European Com-
munity’s Seventh Framework Program (FP7 2007e2013)/ERC Grant
Please cite this article in press as: Diers, E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.01.006

E. Diers et al. / Tetrahedron xxx (2013) 1e9
9
ꢀ
Ackermann, L. Org. Lett. 2012, 14, 4110e4113; (o) Thirunavukkarasu, V. S.;
Hubrich, J.; Ackermann, L. Org. Lett. 2012, 14, 4210e4213.
13. Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew. Chem., Int. Ed. 2009,
48, 6045e6048.
12. For representative subsequent reports from other research groups, see: (a)
Dastbaravardeh, N.; Schnuerch, M.; Mihovilovic, M. D. Org. Lett. 2012, 14,
3792e3795; (b) Bergman, S. D.; Storr, T. E.; Prokopcova, H.; Aelvoet, K.;
Diels, G.; Meerpoel, L.; Maes, B. U. W. Chem.dEur. J. 2012, 18, 10393e10398;
(c) Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am. Chem. Soc.
2011, 133, 10161e10170; (d) Stefane, B.; Fabris, J.; Pozgan, F. Eur. J. Org.
Chem. 2011, 3474e3481; (e) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.;
Dixneuf, P. H. Angew. Chem., Int. Ed. 2010, 49, 6629e6632; (f) Arockiam, P.;
Poirier, V.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2009,
11, 1871e1875.
14. Presented in part at the fourth International Symposium on Advances in Syn-
thetic and Medicinal Chemistry (ASMC), St. Petersburg, August 2011
15. The connectivity of product 3aa was unambiguously established by X-ray dif-
fraction analysis
16. Ackermann, L.; Lygin, A. V. Org. Lett. 2011, 13, 3332e3335.
17. Ackermann, L.; Diers, E.; Manvar, A. Org. Lett. 2012, 14, 1154e1157.
18. For a related recent observation, see: Aihara, Y.; Chatani, N. Chem. Sci. 2013, 4 ,
664e670.
19. Alvarez-Builla, J.; Vaquero, J. J.; Barluenga, J. Modern Heterocyclic Chemistry;
Wiley-VCH: Weinheim, Germany, 2011.
Please cite this article in press as: Diers, E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.01.006