Amination of heterocyclic compounds with O-benzoylhydroxylamine derivatives

Article abstract of DOI:10.1021/ol701730r

The N-amination of heterocyclic compounds 1a - k with O- benzoylhydroxylamine derivatives 5 was developed and demonstrated to be a superior alternative to existing N-amination methods. A structure - reactivity relationship study was performed on variously

Full text of DOI:10.1021/ol701730r

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3821-3824
Amination of Heterocyclic Compounds
with O-Benzoylhydroxylamine
Derivatives
Luca Parlanti, Robert P. Discordia, John Hynes, Jr.,† Michael M. Miller,†
Harold R. O’Grady,† and Zhongping Shi*
Departments of Process Research and DeVelopment and Drug DiscoVery Chemistry,
Bristol-Myers Squibb Research & DeVelopment, P.O. Box 4000,
Princeton, New Jersey 08543
zhongping.shi@bms.com
Received July 20, 2007
ABSTRACT
The N-amination of heterocyclic compounds 1a
alternative to existing N-amination methods.
benzoylhydroxylamine derivatives, leading to the discovery of the novel and more efficient aminating reagents 5h and 5i.
−k with O-benzoylhydroxylamine derivatives 5 was developed and demonstrated to be a superior
A
structure reactivity relationship study was performed on variously substituted O-
−
The amination of nitrogen and carbon nucleophiles is an
attractive tool for synthetic and medicinal chemists and can
provide easy access to a variety of useful substances. Num-
erous NH2-transfer agents have been previously described
in the literature,1 including a variety of hydroxylamine-based
compounds, such as the O-acyl,2 O-alkyl,3 O-sulfonyl,1a,4
O-nitrophenyl,5 and O-diarylphosphinyl6 derivatives. How-
ever, due to their limited availability,1,6a,7 stability,1,2c,4a as
well as the safety concerns around their handling,5a,7 the latter
class of compounds has seen limited utility in large scale
processes. Therefore, seeking and developing safe, conve-
nient, and efficient reagents and processes for the direct
amination of carbon and nitrogen nucleophiles continues to
be an area of interest in organic synthesis.2a,5a,6a,7
A general N-amination methodology for pyrroles and
indoles was recently developed by researchers at Bristol-
Myers Squibb using an in situ prepared ethereal monochlor-
amine (NH2Cl) solution to produce the corresponding amino
pyrroles and indoles in high yield.7 This method was
successfully applied on a multigram scale and provided an
easy entry to 11 N-amino heterocycles. Nevertheless, despite
its high efficiency for NH2+ transfer and operational simplic-
(5) (a) Boyles, D. C.; Curran, T. T.; Partlett, R. V.; Partlett, T. T. Org.
Process Res. DeV. 2002, 6, 230. (b) Radhakrishna, A. S.; Loudon, G. M.;
Miller, M. J. Org. Chem. 1979, 44, 4836. (c) Bellettini, J. R.; Olson, E. R.;
Teng, M.; Miller, M. J. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 3, pp 2189-2190. (d)
Mavunkel, B.; Perumattam, J. J.; Tester, R. W.; Dugar, S. Int. Pat. Appl.
Publ., 2004, 36 pp, Cont.-in-part of U.S. Ser. No. 36,293. PTC/US2003/
021888 WO 2004/007462 A1.
(6) (a) Smulik, J.; Vedejs, E. Org. Lett. 2003, 5, 4187. (b) Boche, G. In
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: New York, 1995; Vol. 4, pp 2240-2242. (c) Boche, G.; BernHeim,
M.; Schott, W. Tetrahedron Lett. 1982, 23, 5399. (d) Colvin, E.; Kirby,
G.; Wilson, A. Tetrahedron Lett. 1982, 23, 3835.
† Department of Drug Discovery Chemistry.
(1) (a) Tamura, Y.; Minamikaw, J.; Ikeda, M. Synthesis 1977, 1. (b)
Erdik, E. Tetrahedron 2004, 60, 8747.
(2) (a) Shen, Y.; Friestad, G. K. J. Org. Chem. 2002, 67, 6236. (b)
Carpino, L.; Giza, C.; Carpino, B. J. Am. Chem. Soc. 1959, 81, 955. (c)
Marmer, W.; Maerker, G. J. Org. Chem. 1972, 37, 3520. (d) Boche, G.
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: New York, New York, 1995; Vol. 5, pp 3270. (e) Carpino, L. A.
J. Org. Chem. 1965, 30, 736. (f) Carpino, L. A. J. Org. Chem. 1965, 30,
321. (g) Johnson, J. S.; Berman, A. M. J. Org. Chem. 2005, 70, 364.
(3) Oguri, T.; Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1975, 23, 173.
(4) (a) Carpino, L. J. Am. Chem. Soc. 1960, 82, 3133. (b) Taylor, E.;
Sun, J.-H. Synthesis 1980, 801.
(7) Hynes, J.; Doubleday, W.; Dyckman, A.; Godfrey, J.; Grosso, J.;
Kiau, S.; Leftheris, K. J. Org. Chem. 2004, 69, 1368.
10.1021/ol701730r CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/24/2007

ity on a laboratory scale, the above procedure had limited
potential on a multikilo scale due to a significantly lower
conversion (70%) observed upon scale-up. In addition, the
low solubility of NH2Cl in organic solvents resulted in
elevated reaction volumes and poor efficiency.
The pyrrolotriazine derivative 4 is a key intermediate in
the synthesis of several biologically active compounds under
investigation at Bristol-Myers Squibb.8 The compound is
obtained from the amino pyrrole 3a, prepared from pyrrole
1a through N-amination (Scheme 1). The need for high
was estimated to be ∼5 days (0.28 M) with partial conversion
(∼3%) to p-nitrobenzohydroxamic acid 7 also occurring
(Scheme 2). Addition of water (10% in NMP) did not impact
the hydrolysis/isomerization significantly. However, the
presence of hydroxylamine did accelerate the hydrolysis/
isomerization process reducing the half-life of 5a to 3 h and
significantly increasing the level of 7 (∼15%). It is interesting
to point out that 5a is more stable in acetonitrile with <1%
hydrolysis in 40 h. In such conditions, the observed half-
life was ∼6 days with 7 being the major degradation product
(∼40%). On the other hand, the pure crystalline form of 5a
is stable at room temperature for up to 6 months or at 0 °C
for more than 2 years. This provides a reasonable shelf life
for storage and use in manufacturing. Furthermore, the
thermal stability analysis of 5a displayed exothermic behav-
ior with activity at 100.2 °C (641.2 J/g) and 161.9 °C (656.5
J/g), which offers a reasonable safety window when operating
at room temperature.
Scheme 1. Preparation of Pyrrolotriazine 4
When treated with potassium t-butoxide in NMP, 1a
converted to anion 2a, which reacted with 5a to provide the
desired N-amino pyrrole 3a. The reaction was complete in
15 min at room temperature using optimized conditions
(1.05-1.10 equiv of base and 1.1-1.2 equiv of 5a). The
highest conversion (92%) was achieved in anhydrous NMP,
and data clearly indicated a negative effect of moisture. After
further fine-tuning, the above procedure was then progres-
sively scaled-up to eventually produce multihundred kilogram
lots of amino pyrrole 3a and subsequently pyrrolotriazine 4
in 70% overall yield.
volumes of 4, along with the previously discussed limitations
of the available amination protocols, led us to focus our
efforts on seeking new reagents with improved physical and
chemical properties, to enable large scale access to the above
compounds.
As this new methodology was proven efficient for 1a, its
scope was then extended to various heterocyclic compounds
including pyrroles 1b-1c, indoles 1d-1g, imidazoles 1h and
1i, pyrazole 1j, and carbazole 1k (see Table 1 for results).
Amination of 1a,b,d,e with 5a gave results similar to those
obtained with monochloramine, including the same chemose-
lective amination of the pyrrole ring in the case of substrate
1b containing an amide substituent.7 It was noted that
pyrroles with more electron-withdrawing groups, such as 1a,
gave higher conversion (92%) than those with more electron-
donating groups, such as 1c (84%). All four indole substrates
examined, 1d-1g, gave excellent conversions (82-92%).
It was found that the aminated product 3g from formylindole
1g was not stable during isolation, ostensibly due to the
reaction of the aldehyde and the amino group polymerizing
through the Schiff base. The present amination method also
worked well for pyrazole 1j and carbazole 1k with conver-
sions of 95% and 80%, respectively. However, amination
of imidazole 1h and 1i only provided moderate conversions
of 59% and 61%, respectively. The conversion was improved
to 75% and 76% when potassium t-butoxide was replaced
with potassium bis(bistrimethylsilyl)-amide.
Friestad and co-workers reported the NH2+ transfer to the
nitrogen of a cyclic carbamate through the use of O-(4-nitro-
benzoyl)hydroxylamine 5a (Scheme 1).2a To the best of our
knowledge, the application of O-benzoylhydroxylamines to
the N-amination of pyrrole, indole, imidazole, or pyrazole
substrates has not been previously disclosed, although
O-mesitoylhydroxylamine is known to react with pyrroles2e
and carbazoles2f to afford the related amino compounds in
low yields, 37% and 60%, respectively. Because 5a appeared
to be an accessible compound fairly easy to synthesize from
common starting materials,2b,c we decided to evaluate its
reactivity toward pyrrole 1a.
After a brief optimization of the literature methods,2b,9 we
developed a process capable of providing 5a in a single step
from p-nitrobenzoyl chloride and N-Boc-hydroxylamine in
80% yield and 99% purity by HPLC (Scheme 2). During
our work, we also observed that 5a is relatively unstable in
NMP solutions. After 16 h, ∼2% hydrolysis to benzoic acid
6 was observed at ambient conditions. The half-life of 5a
Scheme 2. Preparation of 5a and Its Hydrolysis/Isomerization
to 6 and 7
Having demonstrated the generality of this amination
reaction on a series of heterocyclic compounds with various
(8) Godfrey, J. D.; Hynes, J.; Dyckman, A. J.; Leftheris, K.; Shi, Z.;
Wrobleski, S. T.; Doubleday, W. W.; Grosso, J. A. U. S. Pat. Appl. Publ.,
2003, 36 pp, Cont.-in-part of U.S. Ser. No. 36,293. US 2003186982 A1
20031002 CAN 139:292275 AN 2003:777390.
(9) (a) Jencks, W. P. J. Am. Chem. Soc. 1958, 80, 4581. (b) Jencks, W.
P. J. Am. Chem. Soc. 1958, 80, 4585.
3822
Org. Lett., Vol. 9, No. 19, 2007

bilized enolates using phosphine-based hydroxylamine de-
rivatives. This was rationalized assuming a proton transfer
from the aminating agents (pKa 20-24) quenching the
enolates (pKa 22-24).6a However, pyrrole 1a has a much
lower pKa (8.7),7 which should exclude the possibility of
proton transfer from 5a to the preformed anion 2a.
Table 1. Results and Comparison of the Amination Reactions
with 5a, 5h, and 5i
We surmised that the incomplete conversion of 1a is likely
due to the presence of residual moisture, which can compete
with the pyrrole to react with 5a. As noted above, amination
in anhydrous solvents provided the highest conversions. In
line with this hypothesis, addition of water (1 equiv) to the
reaction mixture led to a significantly lower conversion
(78%). Also, we had demonstrated that hydroxylamine
catalyzes the conversion of O-p-nitrobenzoylhydroxylamine
(5a) to p-nitrobenzohydroxamic acid 7.9 Under the reaction
conditions and in the presence of residual moisture, hy-
droxylamine could be generated from hydrolysis of 5a,
initiating the transformation to 7 (Scheme 3). Quenching of
Scheme 3. Rate-Controlled Reactions of 5a with Pyrrole
Anion 2a and Water
the reactive anion 2a to 1a by proton transfer from 7 (Scheme
3) is then the most likely cause for the incomplete reaction.10
As expected, addition of excess 5a (>2 equiv) did not
improve the conversion.
Because our experimental results indicate that amination
of 1a with 5a (>90%) was inherently faster than the reaction
of 5a with water, we hypothesized that we might favorably
tune the reactivity and therefore the selectivity of O-ben-
zoylhydroxylamine derivatives in amino-transfer reactions
by replacing the nitro group with less electronegative
substituents. To evaluate this hypothesis, a series of substi-
tuted O-benzoylhydroxylamine analogues were prepared
from the corresponding benzoyl chloride, using a method
similar to that described for 5a (Table 2). Compounds 5b,
5d, 5e, and 5g are novel, whereas 5h11 has been reported as
an unisolated intermediate converted in situ to an oxime with
acetone. Compounds 5c2c and 5f2b,9a are known. The crystal-
a
HPLC conversion after 0.5-3 h at room temperature (Waters XTerra
RP-18, 3.5 µm, 4.6 × 50 mm, 1-100% 0.05% TFA water/acetonitrile
(95:5); 0.05% TFA water/acetonitrile (5:95), 2.5 mL/min, 8 min gradient,
b
c
256 nm). Isolated. KHMDS was used as base.
functional groups, we then tried to further improve the
reaction to maximize conversions. However, efforts to
improve the conversion of 1a to 3a under various conditions
(including using excess base and/or reagent 5a) were
unsuccessful. The reaction always suffered from incomplete
conversion, leaving 7-10% of residual 1a. Vedejs and co-
workers also reported low yields for amination of nonsta-
(10) Hydroxamic acid 6 was reported to have a pKa of 8.9. Ventura, O.
N.; Rama, J. B.; Turi, L.; Dannenberg, J. J. J. Am. Chem. Soc. 1993, 115,
5754.
(11) King, F. D.; Walton, D. R. M. Synthesis 1975, 788.
Org. Lett., Vol. 9, No. 19, 2007
3823

Table 2. Amination of 1a with O-Benzoylhydroxylamine
Analogues 5a-5i
compound 5
R ) (yield)a
substituent
constant (s)
pKa of
BzOH
conversionb
a, 4-NO2 (85%)
b, 4-F (84%)
c, 3-Cl (77%)
d, 4-Cl (89%)
e, 4-Br (82%)
f, 4-Hc
0.81
0.15
0.37
0.24
0.26
0
-0.14
-0.12
-
3.45
4.15
3.84
3.99
3.97
4.19
4.37
4.50
4.36
92
93
95
95
96
91d
94d
97
96
g, 4-Mec
h, 4-OMe (89%)
i, 2,4-dimethoxy (84%)
a
b
Yield for preparation of reagent 5. HPLC % conversion after 0.5-
3.0 h at room temperature (Waters XTerra RP-18, 3.5 µm, 4.6 × 50 mm,
10% water/acetonitrile to 0.2% H3PO4/water, 2.5 mL/min, 8 min gradient,
c
d
256 nm). Oil, not stable. Because pure 5f and 5g were not stable, a
solution of 5f or 5g in NMP was prepared in situ from its related
methanesulfonate salt and used for the amination.
Figure 1. Kinetic constants for amination of 1a with 5a, 5c, and
5h.
line analogues 5b-e and 5h are stable at room temperature.
However, 5f and 5g are oils and unstable at room temperature
with significant degradation in 1 h.2b,11
analogous to those with 5h, and a higher conversion (96%
vs 91%) was obtained for pyrrole 1c. Furthermore, 5i was a
more convenient compound to handle due to its higher
melting point (66.0-67.0 °C vs 34.0-35.0 °C for 5h).
In summary, a general, efficient, and practical N-amination
of heterocyclic compounds using O-benzoylhydroxylamine
derivatives was developed, providing a superior alternative
to other existing methods. To optimize the methodology, the
structure-reactivity relationship of O-benzoylhydroxylamine
analogues 5a-h was explored, thereby leading to the
discovery of the novel and more efficient reagents 5h and
5i.
The results from the reactions of pyrrole 1a with 5a-h
are summarized in Table 2. As expected, 5h, bearing the
strongest electron-donating group, was the least reactive
reagent and provided the highest conversion (97%). The
reaction of 5h was significantly slower than 5a, requiring
more than 2 h (at 20 °C) to reach the end point, as compared
to 15 min with 5a. Similarly, hydrolysis of 5h in DMSO-
water was also much slower, with a half-life of 26 h, as
compared to 1.8 h for 5a. Significant rate differences were
observed across the different reagents. Kinetic constants for
the N-amination reactions with the p-nitro (5a), m-chloro
(5c), and p-methoxy (5h) benzoylhydroxylamines were
calculated as shown in Figure 1. A conversion of 92%, 95%,
and 97% was obtained with 5a, 5c, and 5h in 15, 60, and
120 min, respectively, which confirmed our rate control
assumption.
Acknowledgment. The Authors would like to thank the
Department of Discovery Analytical Sciences for HRMS and
pKa determinations, Dr. Francis J. Okuniewicz (PR&D) for
thermal evaluations of 5a, and Professor G. K. Friestad
(University of Vermont) for useful discussions regarding 5a.
+
As 5h was demonstrated to be a superior NH2 transfer
agent for pyrrole 1a, its application was then extended to
other heterocyclic compounds 1b-1k. As expected, the
conversion for all substrates was significantly improved, from
59-95% (with 5a) to 84-99% (with 5h) (Table 1). Another
novel compound 5i (R ) 2,4-dimethoxy) was also prepared
similarly to 5h. In most cases, this reagent provided results
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL701730R
3824
Org. Lett., Vol. 9, No. 19, 2007