Palladium-catalyzed coupling of pyrid-4-yl nonaflates with methyl diazoacetate

Article abstract of DOI:10.1055/s-0031-1290398

Palladium-catalyzed couplings of pyrid-4-yl nonaflates with methyl diazoacetate are described. After optimization of the reaction conditions the scope of the transformation proved to be fairly broad and a series of pyrid-4-yl-substituted methyl diazoacetates was prepared in generally high yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290398

1670▌
LETTER
letter
Palladium-Catalyzed Coupling of Pyrid-4-yl Nonaflates with Methyl Diazo-
acetate
Palladium-Catalyzed Coupling of Diazoacetates
Christian Eidamshaus, Paul Hommes, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received: 16.04.2012; Accepted: 03.05.2012
Wang 2007
N2
Abstract: Palladium-catalyzed couplings of pyrid-4-yl nonaflates
with methyl diazoacetate are described. After optimization of the
reaction conditions the scope of the transformation proved to be
fairly broad and a series of pyrid-4-yl-substituted methyl diazoace-
tates was prepared in generally high yields.
OEt
N2
H
I
O
CO2Et
R
R
[Pd(PPh3)4], MeCN
DBU, TBAB, 45 °C
Key words: pyridines, bipyridines, nonaflates, palladium catalysis,
cross couplings, diazoacetate
1
2
Frantz 2011
N2
OEt
H
Palladium-catalyzed coupling reactions have evolved into
one of the most efficient methods for the construction of
C–C bonds.1 Coupling between aryl halides and metal-
organic species have been well-established for many
years. In contrast, palladium-catalyzed couplings employ-
ing CH-active precursors as carbon nucleophiles have
only recently been developed. Based on the pioneering
O
R
OTf
R
CO2Et
[Pd(PPh3)4], DMF
NMM, r.t.
O
N2
O
3
4
Scheme 1 Literature examples for the palladium-catalyzed coupling
of ethyl diazoacetate with aryl iodides and electron-deficient alkenyl
work of Hartwig and Buchwald on the intermolecular triflates
coupling of enolates derived from ketones, esters and am-
ides,2 the use of other CH-acidic compounds such as ni-
As we demonstrated earlier, pyrid-4-yl nonaflates 11 can
triles, nitroalkanes, aldehydes etc. has attracted growing
interest in palladium-catalyzed arylation processes over
the last years.3 Recently, two reports have been published
describing the use of alkyl diazoacetates as coupling part-
ners: Wang and co-workers developed a protocol for the
palladium-catalyzed coupling of vinyl and aryl iodides
with ethyl diazoacetate to compounds 2,4 and Frantz et al.
reported the coupling of acceptor-substituted enol
triflates5 providing products such as 4 (Scheme 1).
be prepared through a simple two-step process utilizing
a TMSOTf-promoted cyclocondensation of β-ketoen-
amides 10 followed by a nonaflation step with the inter-
mediate 4-hydroxypyridines (Scheme 2).8 Two routes
have been developed for the preparation of the required β-
ketoenamides: a multi-component approach based on the
reaction of lithiated alkoxyallenes 5, nitriles 6, and car-
boxylic acids 7 (Scheme 2, route A)9 or the acylation of
simple enaminoketones 8 with acyl chlorides 9 (route
B).10 In addition to a series of highly substituted pyridine
derivatives, we also prepared enantiopure pyridine deriv-
atives with side chains bearing stereogenic centers in the
2- and/or 6-position.11 Some of these new pyridines
proved to be good ligands for asymmetric transforma-
tions, including the addition of zinc organyls to aldehydes
or the iridium-catalyzed hydrogenation of olefins.12
Over the last years we have systematically investigated
the behavior of pyrid-4-yl nonaflates in various cross-
coupling processes.6 Intrigued by the reports of the two
groups mentioned above, we wanted to identify reaction
conditions for palladium-catalyzed couplings of pyrid-4-
yl nonaflates with alkyl diazoacetates, which should lead
to structurally interesting new pyrid-4-yl diazoacetates.
Only a few reports describe the preparation and use of
pyridyl diazoacetates, and the majority of the synthetic
routes are based on diazo group transfer processes em-
ploying pyrid-4-yl acetates as starting materials.7 Hence,
the palladium-catalyzed coupling between pyrid-4-yl
nonaflates and alkyl diazoacetates would present a useful
and flexible alternative to access these versatile com-
pounds.
As we had large quantities of the enantiopure pyridyl nona-
flate 13a available from a previous investigation, we de-
cided to use this compound in our optimization studies. In
a first experiment, 13a was reacted with methyl diazoace-
tate under reaction conditions similar to those reported by
Frantz and co-workers5 (Table 1, entry 1). Although the
desired product 14a could be isolated, the yield was only
moderate and the reaction was rather slow. Even after
three days at room temperature, complete conversion was
not achieved. Unfortunately, neither higher reaction tem-
peratures nor changes in the stoichiometry of the reagents
led to higher conversions.
SYNLETT 2012, 23, 1670–1674
Advanced online publication: 14.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290398; Art ID: ST-2012-D0334-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed Coupling of Diazoacetates
1671
R2
R3
R4
C
N
OR
6
route A
route B
•
R4
R4
O
+
O
R1
Li
R1
R1
R5
Pd catalysis
R4
NH
O
1) TMSOTf, Et3N
2) NaH, NfF
N
5
O
O
N
OH
O
R1
S
7
9
R3
O
C4F9
= ONf
R3
R3
ref.
9b,10,11c
NH2
O
R2
R2
10
R2
R1
R4
+
R3
11
12
Cl
R2
8
Scheme 2 Synthesis of highly substituted pyrid-4-yl nonaflates 11 by TMSOTf/base-promoted cyclocondensations of β-ketoenamides 10 fol-
lowed by nonaflations and palladium-catalyzed transformations of 11 leading to specifically substituted pyridine derivatives 12
We next applied the reaction conditions reported by Wang rious effect, leading to a low yield of 22% (Table 1, entries
and co-workers.4 Although this led to complete conver- 4 and 5). By screening different amine bases, we found
sion of pyridyl nonaflate 13a within 24 hours, the yield of that triethylamine gave the best results; 72% of the desired
the isolated coupling product 14a was only slightly im- coupling product 14a could be isolated after only four
proved (Table 1, entry 2).
hours reaction time (Table 1, entry 6). Unexpectedly, the
use of Hünig’s base gave a dramatically lower yield (Ta-
ble 1, entry 7). We also tested whether other palladium
catalysts were capable of promoting the coupling reaction,
but neither [Pd2(dba)3]/P(t-Bu)3 nor [PdCl2(PPh)3] afford-
ed product 14a (Table 1, entries 8 and 9). Finally, in the
absence of any palladium catalyst no product formation
was observed, ruling out a competitive addition–elimina-
tion process (Table 1, entry 10).
To identify the origin of the observed higher reaction rates
under Wang’s conditions, a systematic screening was un-
dertaken in which all parameters were varied. We found
that the use of TBAB as an additive – in contrast to the
coupling of aryl iodides – had no significant influence on
the reaction efficiency (compare Table 1, entries 2 and 3).
However, both the base and the solvent seem to strongly
influence the reaction efficacy. The use of N-methylmor-
pholine (NMM) instead of DBU led to significantly di- With the optimized reaction conditions (Table 1, entry
minished yields and a change of the solvent from 6),13 we then started to evaluate the substrate scope of the
acetonitrile to DMF proved to have an even more delete- process with respect to different substitution patterns at
Table 1 Optimization of the Palladium-Catalyzed Coupling of Methyl Diazoacetate with Pyrid-4-yl Nonaflate 13a
N2
MeO2C
N2
OMe
ONf
H
O
Pd catalysis
Ph
Ph
N
Me
N
Me
OTBS
OTBS
13a
14a
Entry
Catalyst
Conditionsa
Time (h)
Yield (%)
1
2
Pd(PPh3)4 (5 mol%)
Pd(PPh3)4 (10 mol%)
Pd(PPh3)4 (10 mol%)
Pd(PPh3)4 (10 mol%)
Pd(PPh3)4 (10 mol%)
Pd(PPh3)4 (10 mol%)
Pd(PPh3)4 (10 mol%)
Pd2(dba)3 (5 mol%)
NMM, DMF, r.t.
72
24
24
24
24
4
44b
49
45
35
22
72
8
DBU, MeCN, TBAB, 45 °C
DBU, MeCN, 45 °C
NMM, MeCN, 45 °C
DBU, DMF, 45 °C
3
4
5
6
Et3N, MeCN, 45 °C
(iPr)2NEt, MeCN, 45 °C
7
24
24
24
24
8
[HP(t-Bu)3][BF4] (10 mol%) NMM, DMF, r.t.
Et3N, MeCN, 45 °C
–
9
PdCl2(PPh3)2 (5 mol%)
No catalyst
–
10
DBU, MeCN, 45 °C
–
a NMM = N-methylmorpholine; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; TBAB = tetra-n-butylammonium bromide.
b Complete conversion was not achieved.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1670–1674

1672
C. Eidamshaus et al.
LETTER
Table 2 Substrate Scope of the Palladium-Catalyzed Coupling of Pyrid-4-yl Nonaflates 13 with Methyl Diazoacetate
N2
MeO2C
N2
OMe
ONf
H
R3
R2
R3
R2
O
[Pd(PPh3)4], Et3N
MeCN, 45 °C
R6
N
R6
N
13
14
Entry
1a
Pyrid-4-yl Nonaflate
Product
Time (h) Yield (%)
MeO2C
N2
ONf
13a
13b
13c
14a
14b
14c
4
72
84
87
N
Me
N
Me
OTBS
OTBS
MeO2C
N2
ONf
2b
1.5
1.5
N
Me
N
Me
MeO2C
N2
ONf
N
3c
Me
N
Me
N
N
CO2Me
CO2Me
N2
NfO
NfO
ONf
N
N2
N
4a
5a
6a
13d
13e
13f
14d
14e
14f
1
93
N
N
N
N
N
Me
Me
Me
CO2Me
Me
CO2Me
N2
ONf
N2
S
1
77
S
N
N
N
Me
Me
Me
Me
MeO2C
N2
ONf
OMe
S
OMe
S
72
28 (53)d
N
N
S
S
MeO2C
N2
ONf
7c
13g
14g
96
37 (81)d
N
Me
N
Me
N
N
a Pd(PPh3)4 (10 mol%) was used.
b Pd(PPh3)4 (5 mol%) was used.
c Pd(PPh3)4 (7 mol%) was used.
d Yield based on recovered starting material given in parenthesis.
Synlett 2012, 23, 1670–1674
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed Coupling of Diazoacetates
1673
the pyridine ring; the results are summarized in Table 2.
Regardless of the electronic nature of the pyridine ring
substituents, the coupling reactions were complete within
a few hours (typically within 1–4 h) and good yields were
obtained (Table 2, entries 1–5). Substituents in the 3-posi-
tion, however, seem to have a significant impact on the re-
action efficacy. Hence, 3-methoxy-2,6-(dithienyl)pyrid-
4-yl nonaflate (13f) and 3-benzyl-substituted pyridine de-
rivative 13g were transformed at significantly lower rates
than all other substrates tested, and full conversions into
the corresponding pyrid-4-yl methyl diazoacetates were
not achieved within three days reaction time (Table 2, en-
tries 6 and 7); considerable amounts of starting material
were isolated in these experiments. Apart from this limi-
tation, the developed conditions proved to be rather gen-
eral and it could be shown that alkyl, aryl, and heteroaryl
substituents in the 2- or 6-position of the pyridine ring
were well-tolerated (Table 2, entries 2–5).
Acknowledgment
The authors thank the Studienstiftung des Deutschen Volkes (PhD
fellowship to C.E.), the Deutsche Forschungsgemeinschaft (GK
1582) and Bayer Healthcare for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
(1) Metal-Catalyzed Cross Coupling Reactions, 2nd ed.;
Diederich, F.; de Meijere, A., Eds.; Wiley-VCH: Weinheim,
2004.
(2) Reviews: (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res.
2003, 36, 234. (b) For palladium-catalyzed arylations of
amines and α-CH acidic compounds, see: Schlummer, B.;
Scholz, U. In Modern Arylation Methods; Ackermann, L.,
Ed.; Wiley-VCH: Weinheim, 2009, 69. (c) Colacot, T. J.;
Johansson, C. C. C. Angew. Chem. Int. Ed. 2010, 49, 676;
Angew. Chem. 2010, 122, 686; and references cited in these
reviews. (d) For a very early case of an intramolecular
coupling involving ketone enolates, see: Khan, F. A.;
Czerwonka, R.; Reissig, H.-U. Synlett 1996, 533.
(3) (a) Tsuji, J. Palladium Reagents and Catalysts - New
Perspectives for the 21st Century; John Wiley & Sons:
Chichester, 2004, 357–372. (b) Miura, M.; Satoh, T. Top.
Organomet. Chem. 2005, 14, 55. (c) Bellina, F.; Rossi, R.
Chem. Rev. 2010, 110, 1082.
Remarkably, the preparation of 2,2′-bipyridine and
2,2′:6′,2′′-terpyridine derivatives 14c and 14d could also
be achieved in excellent yields (Table 2, entries 3 and 4).
The twofold coupling required for the conversion of 13d
into bis(diazo) compound 14d proceeded with particular-
ly high efficacy. An additional practical aspect of the de-
veloped reaction conditions is the fact that, in some cases,
the generated pyrid-4-yl-substituted methyl diazoacetates
directly precipitate from the reaction mixture. Thus, com-
pounds 14d and 14e could be isolated in analytical pure
form upon simple filtration. In addition, as already shown
in the optimization studies, TBS-protected hydroxymeth-
yl-substituted pyridyl nonaflates can be coupled without
touching the functionalized sidechain. The high yield of
thienyl-substituted compound 14e (Table 2, entry 5) dem-
onstrates that the presence of a sulfur-containing group
does not hamper the coupling step.
(4) Peng, C.; Cheng, J.; Wang, J. J. Am. Chem. Soc. 2007, 129,
8708.
(5) Babinski, D. J.; Aguilar, H. R.; Still, R.; Frantz, D. E. J. Org.
Chem. 2011, 76, 5915; In this report, most of the prepared
enol triflates are converted without purification into the
diazo compounds, which then underwent an electrocyclic
ring closure to provide pyrazole derivatives.
(6) (a) Lechel, T.; Dash, J.; Eidamshaus, C.; Brüdgam, I.; Lentz,
D.; Reissig, H.-U. Org. Biomol. Chem. 2010, 8, 3007.
(b) For a review, see: Högermeier, J.; Reissig, H.-U. Adv.
Synth. Catal. 2009, 351, 2747.
We also briefly examined other aryl and alkenyl nona-
flates. Interestingly, neither phenyl nonaflate nor (Z)-
pent-1-en-1-yl nonaflate14 were transformed into the cor-
responding diazo compounds under the developed reac-
tion conditions. Apparently, only nonaflates containing
electron-deficient substituents are able to undergo the palla-
dium-catalyzed coupling with methyl diazoacetate, which
is in agreement with results obtained by Frantz and co-
workers5 regarding alkenyl triflates.
(7) (a) Tomioka, H.; Ichikawa, N.; Komatsu, K. J. Am. Chem.
Soc. 1993, 115, 8621. (b) Sarkar, T. K.; Gosh, S. K.; Nandy,
S. K.; Chow, T. J. Tetrahedron Lett. 1999, 40, 397.
(c) Muchall, H. M.; Werstiuk, N. H.; Pitters, J. L.;
Workentin, M. S. Tetrahedron 1999, 55, 3767. (d) Sarkar,
T. K.; Ghosh, S. K.; Chow, T. J. J. Org. Chem. 2000, 65,
3111. (e) Davies, H. M. L.; Townsend, R. J. J. Org. Chem.
2001, 66, 6595. (f) Sarkar, T. K.; Basak, S.; Slanina, Z.;
Chow, T. J. J. Org. Chem. 2003, 68, 4206.
(8) (a) Flögel, O.; Dash, J.; Brüdgam, I.; Hartl, H.; Reissig,
H.-U. Chem. Eur. J. 2004, 10, 4283. (b) For a review, see:
Lechel, T.; Reissig, H.-U. Pure Appl. Chem. 2010, 82, 1835.
(9) (a) Dash, J.; Lechel, T.; Reissig, H.-U. Org. Lett. 2007, 9,
5541. (b) Lechel, T.; Dash, J.; Hommes, P.; Lentz, D.;
Reissig, H.-U. J. Org. Chem. 2010, 75, 726. (c) Bera, M. K.;
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(b) Hommes, P.; Jungk, P.; Reissig, H.-U. Synlett 2011,
2311.
In conclusion, we have established an efficient method for
the preparation of pyrid-4-yl-substituted methyl diazo-
acetates 14 based on palladium-catalyzed couplings of
pyrid-4-yl nonaflates 13 with methyl diazoacetate. Diazo-
alkanes of type 14 are interesting compounds that could
undergo a multitude of subsequent reactions such as 1,3-
dipolar cycloadditions or processes involving carbenes.15
Application of a pyrid-4-yl alkyl diazoacetate in surface
modification processes has already been described.16 The
method reported here may also find use in the synthesis of
other new heteroaryl-substituted alkyl diazoacetates.
(11) (a) Eidamshaus, C.; Reissig, H.-U. Adv. Synth. Catal. 2009,
351, 1162. (b) Eidamshaus, C.; Kumar, R.; Bera, M. K.;
Reissig, H.-U. Beilstein J. Org. Chem. 2011, 7, 962.
(c) Eidamshaus, C.; Reissig, H.-U. Eur. J. Org. Chem. 2011,
6056.
(12) Eidamshaus, C.; Reissig, H.-U. Tetrahedron: Asymmetry
2011, 22, 1644.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1670–1674

1674
C. Eidamshaus et al.
LETTER
(13) Palladium-Catalyzed Coupling of Pyrid-4-yl Nonaflates
with Methyl Diazoacetate; Typical Procedure for 14a:
A sealed tube equipped with a stirring bar was charged with
Pd(PPh3)4 (40 mg, 0.034 mmol) and pyrid-4-yl nonaflate
13a11c (210 mg, 0.34 mmol). MeCN (3.5 mL), Et3N (71 μL,
0.51 mmol) and methyl diazoacetate (100 mg, 1.00 mmol)
were added and the resulting solution was stirred at 45 °C for
4 h until complete conversion of the starting material was
observed (reaction monitored by TLC). H2O (20 mL) and
EtOAc (20 mL) were added and the organic layer was
separated. The aqueous layer was extracted with EtOAc
(3 × 20 mL) and the combined organic layers were dried
with Na2SO4, filtered, and the solvent was removed under
reduced pressure. The crude product was purified by flash
column chromatography on silica gel (hexane–EtOAc, 4:1)
to provide pyridyl diazoacetate 14a (101 mg, 72%) as a
yellow oil. [α]D –63.5 (c = 1.0, CHCl3). IR (ATR): 3090–
2860 (C-H), 2095 (CN2), 1715 (C=O), 1595–1550
25.7 (2 × q + s + q, OTBS), 24.6 (q, Me), 52.1 (q, CO2CH3),
77.5 (d, CHPh), 110.3, 115.5 (2 × d, C-3/C-5), 126.2, 127.0,
128.0 (3 × d, Ph), 128.2, 136.0, 143.7, 157.6 (4 × s, Ph, C-
2/C-4/C-5), 164.3 (s, CO); the signal for C=N2 was not
detected. HRMS (ESI-TOF): m/z [M + H]+ calcd. for
C22H30N3O3Si: 412.2051; found: 412.2039.
(14) (a) Lyapkalo, I. M.; Webel, M.; Reissig, H.-U. Eur. J. Org.
Chem. 2002, 1015. (b) Vogel, M. A. K.; Stark, C. B. W.;
Lyapkalo, I. M. Synlett 2007, 2907.
(15) (a) Regitz, M.; Maas, G.; Illger, W. Diazoalkane:
Eigenschaften und Synthesen; Thieme: Stuttgart, 1977.
(b) Doyle, M. P.; Ye, T.; McKervey, M. A. Modern
Catalytic Methods for Organic Synthesis with Diazo
Compounds; John Wiley & Sons: New York, 1998.
(c) Heydt, H. In Science of Synthesis; Vol. 27; Padwa, A.,
Ed.; Thieme: Stuttgart, 2004, 843–935. (d) For reviews, see:
Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(e) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577.
(f) Davies, H. M. L.; Morton, D. Chem. Sov. Rev. 2011, 40,
1857.
(C=C) cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.00, 0.93
(2 × s, 6 H + 9 H, OTBS), 2.49 (s, 3 H, Me), 3.86 (s, 3 H,
CO2CH3), 5.83 (s, 1 H, CHPh), 7.17–7.20, 7.25–7.29, 7.37–
7.38, 7.47–7.49 (4 × m, 1 H + 3 H + 1 H + 2 H, Ph, 3-H/5-
H). 13C NMR (126 MHz, CDCl3): δ = –4.93, –4.91, 18.2,
(16) Pitters, J. L.; Adkinson, D. K.; Griffiths, K.; Norton, P. R.;
Workentin, M. S. Can. J. Chem. 2010, 89, 117.
Synlett 2012, 23, 1670–1674
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