A direct copper-catalyzed route to pyrrolo-fused heterocycles from boronic acids

Article abstract of DOI:10.1016/j.tetlet.2011.11.091

A convenient route to prepare azaindoles and related pyrrolo-fused heterocycles from boronic acids, DBAD (di-tert-butyl-diazodicarboxylate) and enolizable aldehydes and ketones is presented. The reaction proceeds via a one-pot four-step cascade sequence with key steps involving a copper-catalyzed boronic acid coupling to DBAD and a Fischer indolization providing access to a variety of pharmaceutically interesting heterocycles including pyrrolo-pyridines, -pyrimidines, -quinolines, and -isoquinolines from readily available aza-aryl boronic acid precursors.

Full text of DOI:10.1016/j.tetlet.2011.11.091

Tetrahedron Letters 53 (2012) 564–569
’
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A direct copper-catalyzed route to pyrrolo-fused heterocycles
from boronic acids
⇑
Ramsay E. Beveridge , Brian S. Gerstenberger
Worldwide Medicinal Chemistry, Pfizer Global Research & Development, Groton, CT, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 April 2011
Revised 14 November 2011
Accepted 18 November 2011
Available online 25 November 2011
A convenient route to prepare azaindoles and related pyrrolo-fused heterocycles from boronic acids,
DBAD (di-tert-butyl-diazodicarboxylate) and enolizable aldehydes and ketones is presented. The reaction
proceeds via a one-pot four-step cascade sequence with key steps involving a copper-catalyzed boronic
acid coupling to DBAD and a Fischer indolization providing access to a variety of pharmaceutically inter-
esting heterocycles including pyrrolo-pyridines, -pyrimidines, -quinolines, and -isoquinolines from read-
ily available aza–aryl boronic acid precursors.
Keywords:
Azaindoles
Ó 2011 Elsevier Ltd. All rights reserved.
Copper
Fischer rearrangement
Catalysis
Boronic acids
Fused pyrrolo-pyridines (azaindoles) as well as related pyrrolo-
heterocyclic bicycles (e.g., pyrrolo-pyrimidine, -quinoline, and -iso-
quinoline species) are of significant pharmaceutical interest as
indole isosteres.1 In particular, efficient access to pyrrolo-quinoline
and pyrrolo-isoquinoline derivatives represents attractive synthetic
targets as potentially valuable pharmacophores in drug discovery
research since these form the cores of biologically active alkaloids
such as ellipticine2 and the cryptolepines.3
typically rely on pre-formation of the hydrazine precursors by diaz-
otization. In addition, Fischer azaindole synthesis is generally
R2
1eq. n-BuLi (X= Br)
Boc
O
O
R1
Ar
or 5% Cu(OAc)2 (X= B(OH)2)
N
N
X
R3
R1
R3
Ar
HCl/dioxane
one-pot
N
Boc
N
R2
X= Br, B(OH)2
While azaindoles and pyrrolo-heterocycles are indole-type ana-
logues, classical approaches to indole ring formation are not always
amenable to generate these corresponding aza-derivatives.4–6 Spe-
cifically, the Fischer indolization6 which is perhaps the most direct
and robust method to access indoles, is generally not applicable to
pyrrolo-heterocycle synthesis. This is due, in part, to the lack of
commercially available heterocyclic hydrazine precursors, and the
electron-deficient nature of these heterocyclic ring systems toward
the key 3,3-sigmatropic rearrangement step of Fischer indolization.
For these reasons, heterocycles of this type are typically prepared
via alternative multi-step sequences involving pre-formation of
annulation intermediates.4,7–13
Figure 1. One-pot N-functionalized pyrazole formation from aryl-bromides14 or
aryl-boronic acids.15
R1
O
NHBoc
NBoc
Boc
R
R1
R
N
NH
2
5% Cu(OAc)2
B(OH)2
N
N
Het
HCl/dioxane
reflux
650 C, MeOH, 1hr
Het
Het
1
Het
Boc
Not Isolated
Not Isolated
[H+]
R
R
R1
R1
R1
While Fischer indolization represents a more direct approach to
R1
NH
azaindole synthesis, reports of this strategy are rare4b,6c,12 and
-NH3
NH
NH2
R
R
Het
NH2
N
NH2
N
H
H
Het
Het
⇑
Corresponding author at present address: Batey group, Davenport Research
Laboratories, University of Toronto, Dept. of Chemistry, 80 St. George St., Toronto,
ON, Canada.
Azaindoles
Fischer Rearrangement
Scheme 1. Synthetic strategy towards azaindoles and related pyrrolo-heterocycles
from aza–aryl boronic acids.
E-mail addresses: rbeverid@chem.utoronto.ca, ramsay.beveridge@pfizer.com,
ramsaybeveridge@hotmail.com (R.E. Beveridge).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.091

R. E. Beveridge, B. S. Gerstenberger / Tetrahedron Letters 53 (2012) 564–569
565
Table 1
Pyrrolo-pyridine azaindole synthesis from pyridyl-boronic acidsa,23
H
N
R
O
Boc
B(OH)2
R
R1
5% Cu(OAc)2
one-pot
N
N
Het
R1
R2
N
Boc
R2
3
Entry
Boronic acid
Carbonyl
% Yield 3b
B(OH)2
O
H
N
Ph
1a
MeO
MeO
N
N
MeO
MeO
N
(70%)
Ph
B(OH)2
B(OH)2
O
H
N
1b
1c
N
(62%)
OMe
OMe
O
H
N
Me
Me
Br
MeO
N
Br
N
MeO
MeO
(39%)
B(OH)2
B(OH)2
B(OH)2
O
O
H
N
1d
1e
MeO
MeO
MeO
N
N
N
N
(39%)
H
N
Et
MeO
MeO
N
Me
(26%)
Br
O
Ph
H
N
1f
Br
O
Ph
N
(72%)
B(OH)2
c
1g
—
N
N
OMe
B(OH)2
O
O
OMe
H
N
N
1hd
OMe
(61%)
B(OH)2
OMe
c
1id
—
MeO
N
a
Aza–aryl boronic acid (0.75 mmol), di-tbutyl-diazodicarboxylate [(DBAD), 0.5 mmol)], and Cu(OAc)2–H2O (0.05 mmol) were combined in 3 mL MeOH and heated for 1 h
at 65 °C. Cooled to rm. temp then the enolizable carbonyl (0.75 mmol) was added followed by 2 mL 4 N HCl in dioxane and the mixture placed in an 80 °C heating block for
18 h.
b
Isolated yield.
c
No azaindole pdt. observed by LC–MS analysis of the crude reaction mixture.
Similar procedure as described above except 4 wt % H2SO4(aq) at 100 °C for 2 h was used as indolization promoter after removal of dioxane and MeOH in vacuo, see
d
Supplementary data for details.
limited to the formation of only the pyrrolo-pyridine azaindole
class.6c,12 As a result, development of a more general Fischer aza-
indolization method from a larger pool of readily available hetero-
aryl precursors with increased scope, including the synthesis of
other azaindole cores such as pyrrolo-pyrimidine, pyrrolo-quino-
line, and pyrrolo-isoquinoline structures, is a desirable goal.
Recently, we reported on efficient access to N-functionalized
pyrazoles directly from either aryl halides14 or aryl boronic acids15
via their reaction with di-tert-butyl-azodicarboxylate (DBAD)16,17
and 1,3-dicarbonyls in a one-pot format (Fig. 1). Considering that
this pyrazole formation strategy involved in situ generation of an
aryl hydrazide intermediate, we sought to apply readily available

566
R. E. Beveridge, B. S. Gerstenberger / Tetrahedron Letters 53 (2012) 564–569
Table 2
pre-isolation of annulation precursors (Table 1). In agreement
with the observations of Suzenet and co-workers;12b while both
4- and 6-azaindoles can form in these examples, this reaction
was completely regioselective producing the 4-azaindole
exclusively.
In contrast to these results, however, other similar methoxy
substituted pyridyl boronic acids were ineffective toward azaindole
formation even though high conversion to the hydrazone interme-
diates was observed (Table 1, entries 1g and 1i). Interestingly, when
aqueous sulfuric acid was used as indolization promoter,12b 2-
methoxy-3-pyridyl-boronic acid was directly transformed to a tet-
rahydro b-carboline core (Table 1, entry 1h). These indolization
conditions were, however, unsuccessful toward a tetrahydro azain-
dole carboline derived from 2,6-dimethoxy-3-pyridyl-boronic acid
(Table 1, entry 1i).
With these results in hand, we next investigated whether other
commercially available heterocyclic boronic acids could be reacted
in this manner to potentially access a broader scope of pyrrolo-het-
erocycles. Table 2 shows our results toward pyrrolo-pyrimidine
azaindole synthesis from pyrimidine boronic acids. Not surpris-
ingly, while simple 5-pyrimidine boronic acid under these reaction
conditions underwent high conversion to the hydrazone interme-
diate, this species was ineffective toward rearrangement to the
azaindole (Table 2, entry 2a). However, when pyrimidine-boronic
acids functionalized with electron donating amino- or methoxy-
groups were employed, these enabled the key sigmatropic rear-
rangement to occur generating the desired pyrrolo-pyrimidine
azaindoles (Table 2, entries 2b–e).
Continuing toward our goal, we investigated the use of quino-
line- and isoquinoline-boronic acids as precursors toward a ben-
zo-fused class of azaindoles structurally related to biologically
active indolo-quinoline and -isoquinolines (Table 3). Considering
that a variety of quinoline and isoquinoline boronic acid regioisom-
ers are commercially available, these could potentially serve as
convenient precursors to generate a variety of quinoline and iso-
quinoline pyrrolo-fused heterocycles.
Pyrrolo-pyrimidine synthesis from pyrimidyl-boronic acidsa,23
B(OH)2
H
N
O
Boc
N
5% Cu(OAc)2
one-pot
N
N
R1
R1
N
N
R
N
4
R2
Boc
R2
R
Entry Boronic acid
Carbonyl
% Yield 4b
B(OH)2
O
c
2a
—
Ph
Ph
N
N
N
H
N
N
B(OH)2
O
H2N
N
2b
2c
Ph
(55%)
N
NH2
H
N
B(OH)2
O
N
N
N
N
N
H2N
(60%)
F
F
NH2
H
N
Et
B(OH)2
O
N
Me
2d
2e
N
N
H2N
(34%)
NH2
OMe
N
H
N
OMe
O
B(OH)2
Ph
N
MeO
N
Ph
MeO
N
(48%)
Our initial screening in this area involved the reaction of 5-
quinoline-boronic acid, which can only lead to a single indole reg-
ioisomer. In this case, we were pleased to isolate the desired pyr-
rolo-quinoline products in good yield (Table 3, entries 3a and b).
Further investigation showed that 3- and 6-quinoline boronic acids
were also compatible substrates toward pyrrolo-quinoline forma-
tion (Table 3, entries 3c and d). While mixtures of azaindole re-
gio-isomers are possible for these substrates, only a single isomer
was isolated presumably due to a more favorable sigmatropic shift
at these sites. Conversely, 4- and 8-quinoline boronic acid regioi-
somers failed to undergo indolization in this reaction generating
only non-cyclized hydrazone as the main reaction component (Ta-
ble 3, entries 3e and f). Alternatively, isoquinoline boronic acids
were found to be useful precursors toward benzo-fused azaindole
formation. As shown in Table 3, both 4- and 5-isoquinoline boronic
acids provided ready access to isoquinoline indole structures (Ta-
ble 3, entries 3g–j).
As a demonstration of the synthetic utility of this pyrrolo-het-
erocycle synthesis, we have synthesized the b-carboline alkaloid
taraxacine A22 in only two steps from the commercial pyridyl-
boronic acid. After a brief survey of oxidation conditions, DDQ oxi-
dation of the tetra-hydro compound (Table 1, entry 1h) led to a
moderate yield of this alkaloid natural product and demonstrates
the potential of using this strategy to access other related biologi-
cally active b-carboline natural products (Scheme 2).
a
b
c
Identical conditions to those described in Table 1.
Isolated yield.
No azaindole pdt. observed by LC–MS analysis of the crude reaction mixture.
aza-heterocyclic boronic acids in a one-pot strategy to access
azaindole type derivatives 3 via formation of hydrazone 2 and
Fischer-type rearrangement (Scheme 1). Potentially, this strategy
could provide an attractive approach to these pharmaceutically ac-
tive cores due to the range of heteroaryl boronic acids that are
commercially available (or readily prepared under mild condi-
tions)18–20 enabling a more general fused pyrrolo-heterocycle syn-
thesis via the Fischer reaction without pre-formation of annulation
precursors.21
Our early studies in this area focused on the reaction of
methyl-substituted pyridyl boronic acids. While these precursors
were ineffective toward azaindole formation, we did observe high
conversion of these substrates to the corresponding hydrazone
intermediates 2 by LC–MS analysis providing a proof-of-concept
for the first three steps of our proposed azaindole synthesis. Based
on work by the Suzenet group our focus shifted toward pyridyl
boronic acids containing methoxy substitutions.12b We were
pleased to observe that 2-methoxy-5-pyridine boronic acid could
serve as a direct precursor to a variety of azaindoles via our
proposed four-step one-pot reaction. Overall, this sequence
involves an initial copper-catalyzed addition to DBAD followed
by in situ N,N1-di-Boc de-protection, hydrazone formation, and
successful Fischer indolization generating azaindoles without
In summary, this study has shown that a variety of pyrrolo-het-
erocycles can be directly prepared from commercially available
hetero-aryl boronic acids in a simple one-pot copper-catalyzed
four-step cascade sequence. Importantly, pre-formation of annula-
tion precursors is not required in this strategy enabling a more

R. E. Beveridge, B. S. Gerstenberger / Tetrahedron Letters 53 (2012) 564–569
567
Table 3
Pyrrolo-quinoline and pyrrolo-isoquinoline azaindole synthesis from benzo-fused pyridyl-boronic acidsa,23
R1
HN
Het
(HO)2B
O
Boc
R2
5% Cu(OAc)2
one-pot
N
N
R1
X
R2
X
Boc
X= N, CH
5
Entry
Boronic acid
Carbonyl
% Yield 5b
B(OH)2
O
H
N
N
Ph
3a
N
Ph
(65%)
B(OH)2
O
H
N
N
3b
3c
3d
N
(42%)
(HO)2B
O
O
Ph
N
Ph
Ph
N
N
H
(71%)
B(OH)2
Ph
N
N
N
H
(61%)
B(OH)2
O
O
O
Ph
Ph
Ph
c
3e
3f
—
N
c
—
N
B(OH)2
B(OH)2
H
N
3g
3h
3i
N
N
N
N
(45%)
Ph
B(OH)2
B(OH)2
O
O
N
H
N
Ph
Ph
(74%)
N
H
N
(24%)
B(OH)2
O
N
H
N
Ph
Br
3j
N
Br
Ph
(44%)
a
b
c
Identical conditions to those described in Table 1.
Isolated yield.
No azaindole pdt. observed by LC–MS analysis of the crude reaction mixture.
general application of the Fischer indolization reaction toward the
formation of a variety of fused pyrrolo-heterocycles including pyr-
rolo-quinoline and pyrrolo-isoquinoline structures. Specifically,
this approach to pyrrolo-heterocycles may be valuable in future
work toward synthesis of natural product like cores such as carbo-
lines and cryptolepines.

568
R. E. Beveridge, B. S. Gerstenberger / Tetrahedron Letters 53 (2012) 564–569
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1,4-dioxane
900C 2.5 hrs
37%
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Scheme 2. Synthesis of the b-carboline alkaloid taraxacine A.24
Acknowledgments
The authors wish to thank Justin Stroh and Geeta Yalamanchi
for HRMS support, Andrew Butler for NMR support, and Aaron
Smith and Jeremy Starr for help in reviewing this manuscript (all
from Pfizer).
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Supplementary data
Supplementary data (full experimental details characterization
and spectral data (1H, 13C NMRs) for all compounds) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.11.091.
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Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43,
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21. After submission of this manuscript a similar strategy to generate indoles and
some pyrrolo-fused heterocycles was described via fischer reaction of N,N-di-
Boc-hydrazides generated via aryl-lithium addition to DBAD: Inman, M.;
Carbone, A.; Moody, C. J. J. Org. Chem. 2011. doi:10.1021/jo201866c.
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23. General procedure for copper-catalyzed pyrrolo-heterocycle synthesis from boronic
acids: 6-Methoxypyridin-3-ylboronic acid (115 mg, 0.75 mmol), di-tert-
butylazodicarboxylate ‘DBAD’ (115 mg, 0.5 mmol) and Cu(II)OAc–H2O
(5.1 mg, 0.025 mmol) were combined in 3 mL MeOH in a 20 mL scintillation
vial and heated for 1 h at 65 °C. The mixture was cooled to room temperature
and 2-phenylacetaldehyde (90 mg, 0.75 mmol) was added followed by
addition of 2 mL 4 N HCl in dioxane and the mixture was placed in an 80 °C
heating block for 18 h. The reaction was cooled to room temperature and
volatiles were removed in vacuo to give a crude oil which was partitioned
between 25 mL of satd aq NaHCO3 and 100 mL CH2Cl2. Organics were
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Haemers, A.; Pieters, L.; Maes, B. U. W. Tetrahedron 2008, 64, 11802–11809; (h)
Van Baelen, G.; Hostyn, S.; Dhooghe, L.; Tapolcsanyi, P.; Matyus, P.; Lemiere, G.;
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Maes, B. U. W.; Pieters, L. Bioorg. Med. Chem. 2009, 17, 7209–7217; (i) Zhu, X. Y.;
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4. Azaindole synthesis reviews: (a) Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C.
Chem. Rev. 2009, 109, 3080–3098; (b) Popowycz, F.; Merour, J.-Y.; Joseph, B. J.
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extracted, dried (MgSO4), filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography though silica gel using ethyl
acetate in heptanes to elute providing 78 mg (70%) of 5-methoxy-3-phenyl-
dioxane in a scintillation vial then DDQ (70 mg, 0.31 mmol, 2.2 equiv) was
added. Vial was capped and placed in a 90 °C oil bath for 2.5 h then cooled to
room temperature and partitioned between 75 mL CH2Cl2 and 25 mL satd
NaHCO3(aq) and organics separated, dried (MgSO4), filtered and purified by
flash column chromatography through silica gel to provide 10 mg (37%) of pure
taraxacine A as a yellow solid. 1H NMR (300 MHz, CDCl3) d ppm 4.17 (s, 3H)
7.27–7.32 (m, 1H) 7.48–7.54 (m, 2H) 7.57 (dd, J = 5.57, 0.59 Hz, 1H) 7.96 (d,
J = 5.57 Hz, 1H) 8.07 (dd, J = 7.91, 0.88 Hz, 1H) 8.35 (br s, 1H). 13C NMR
1H-pyrrolo[3,2-b]pyridine (Table 1, entry 1a) as
a
yellow solid. 1H NMR
(400 MHz, CDCl3, d): 4.07 (s, 3H) 6.64 (d, J = 8.98 Hz, 1H) 7.22–7.28 (m, 1H)
7.43 (t, J = 7.81 Hz, 2H) 7.51 (d, J = 5.86 Hz, 1H) 7.52 (s, 1H) 8.17 (s, 1H) 8.18–
8.22 (m, 2H). 13C NMR (101 MHz, CDCl3, d): 53.58; 106.01; 116.41; 122.15;
123.67; 125.53; 125.96; 126.51; 128.75; 134.62; 140.30; 160.29. HRMS (m/z):
[M+H]+ for C14H12N2O, calcd, 225.1022; found, 225.1024.
(100 MHz, CDCl3)
123.86; 127.60; 129.51; 135.61; 139.41; 151.25. HRMS (m/z): [M+H]+ for
12H10N2O, calcd, 199.08714; found, 199.08751.
d ppm 53.31; 109.35; 111.71; 120.03; 121.53; 122.26;
24. Synthesis of taraxacine A: 1-Methoxy-6,7,8,9-tetrahydro-5H-pyrido[3,4-
b]indole (Table 1, entry 1 h, 29 mg, 0.14 mmol) was dissolved in 2 mL 1,4-
C