Microwave-promoted Pd-catalyzed cyanation of aryl triflates: A fast and versatile access to 3-cyano-3-desoxy-10-ketomorphinans

Article abstract of DOI:10.1021/ol027256p

(Matrix presented) A methodology for the microwave-promoted conversion of triflates to the corresponding nitriles by using 8% equiv of Pd(Ph ₃P)₄ as the catalyst and 2.0 equiv of Zn(CN)₂ as the cyanide source has been deve

Full text of DOI:10.1021/ol027256p

ORGANIC
LETTERS
2003
Vol. 5, No. 2
201-203
Microwave-Promoted Pd-Catalyzed
Cyanation of Aryl Triflates: A Fast and
Versatile Access to
3-Cyano-3-desoxy-10-ketomorphinans
Ao Zhang and John L. Neumeyer*
Medicinal Chemistry Program, Alcohol and Drug Abuse Research Center, McLean
Hospital, HarVard Medical School, 115 Mill Street, Belmont, Massachusetts 02478
neumeyer@mclean.harVard.edu
Received November 8, 2002
ABSTRACT
A methodology for the microwave-promoted conversion of triflates to the corresponding nitriles by using 8% equiv of Pd(Ph3P)4 as the catalyst
and 2.0 equiv of Zn(CN)2 as the cyanide source has been developed. This method is highly efficient for the preparation of 3-cyano-3-desoxy-
10-ketomorphinans. The reaction was generally completed in 15 min at 200 °C and produced products in greater than 86% yields.
Nitriles are valuable intermediates in organic synthesis and
can be transformed to produce a variety of functionalities
including amide, thiazole, oxazolidone, triazole, and tetra-
zole.1 In the course of our studies on the design and synthesis
of novel ligands for opioid receptors, we became interested
in 3-cyano-3-desoxy-N-alkyl-10-ketomorphinans 2, which
can be recognized as important precursors for a series of
opioid receptor agonists/antagonists.2 Various methods have
been reported for the formation of nitriles including the
stoichiometric reaction of aryl halides with copper(I) cyanide,
the Reissert-Henze cyanation of π-deficient heteroarene
N-oxides, the electrophilic cyanation of π-excessive hetero-
aromatics, and transition-metal-catalyzed displacement of aryl
halides with cyanide ion.3,4 An alternative route to aryl
cyanides is the displacement reaction of aryl triflates with
sodium or potassium cyanide catalyzed with palladium(0)
or nickel(0). These methods achieved limited success.5
(1) (a) Chihiro, M.; Nagamoto, H.; Takemura, I.; Kitano, K.; Komatsu,
H.; Sekiguchi, K.; Tabusa, F.; Mori, T.; Tominaga, M.; Yabuuchi, Y. J.
Med. Chem. 1995, 38, 353-358. (b) Khanna, I. K.; Weier, R. M.; Yu, Y.;
Xu, X. D.; Koszyk, F. J.; Collins, P. W.; Koboldt, C. M.; Veenhuizen, A.
W.; Perkins, W. E.; Casler, J. J.; Masferrer, J. L.; Zhang, Y. Y.; Gregory,
S. A.; Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1634-1647. (c)
Larock, R. C. ComprehensiVe Organic Transformations, A Guide to
Functional Group Preparations; VCH Publishers: New York, 1989. (d)
Diana, G. D.; Cutcliffe, D.; Volkots, D. L.; Mallamo, J. P.; Bailey, T. R.;
Vesico, N.; Oglesby, R. C.; Nitz, T. J.; Wetzel, J.; Giranda, V.; Pevear, D.
C.; Dutko, F. J. J. Med. Chem. 1993, 36, 3240-3250. (e) Medwid, J. B.;
Paul, R.; Baker, J. S.; Brockman, J. A.; Du, M. T.; Hallett, W. A.; Hanifin,
J. W.; Hardy, R. A.; Tarrant, M. E.; Torley, L. W.; Wrenn, S. J. Med.
Chem. 1990, 33, 1230-1241. (f) Judikins, B. D.; Allen, D. G.; Cook, T.
A.; Evans, B.; Sardharwala, T. E. Synth. Commun. 1996, 26, 4351-4367.
(2) Neumeyer, J. L.; Bidlack, J. M.; Zong, R. S.; Bakthavachalam, V.;
Gao, P.; Cohen, D. J.; Negus, S. S.; Mello, N. K. J. Med. Chem. 2000, 43,
114-122.
(3) (a) Andersson, Y.; Långstro¨m. B. J. Chem. Soc., Perkin Trans. 1
1994, 1395-1400. (b) March, J. AdVanced Organic Chemistry; John Wiley
& Sons: New York, 1992. (c) Okano, T.; Kiji, J.; Toyooka, Y. Chem. Lett.
1998, 435-426. (d) Patai, S.; Zabicky, J.; Ed.; John Wiley & Sons: New
York, 1970. (e) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.;
Pipik, B.; King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887-890.
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Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224-8228. (g) Corey, E. J.;
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10.1021/ol027256p CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/19/2002

Recently, the reagent system composed of zinc cyanide and
catalytic palladium tetrakistriphenylphosphine in DMF was
reported to be a general and efficient system for cyanation
of aryl bromides and aryl triflates.6,7 This method has been
successfully applied to the synthesis of 3-cyano-3-desoxy-
naltrexone from the corresponding triflate.8
To achieve the synthesis of nitrile 2, which was a key
immediate for a series of κ opioid receptor selective agonists/
antagonists, we first tried the reagent system of zinc cyanide
and catalytic Pd(Ph3P)4 in DMF by thermal heating (Scheme
1). Under the same conditions reported by Rice,8 triflate 1a
cessful reactions with great efficiency and dramatically
enhanced reaction rates have been disclosed.9 Hallberg7
recently reported the cyanation of aryl and vinyl bromides
with microwave irradiation as the energy source, but there
are no reports on the preparation of nitriles from the
corresponding aryl triflates10,11 under microwave-assisted
conditions. Therefore, we believe we are the first to report
that flash heating by microwave irradiation assists the
formation of nitriles 2 from the triflates 1.
As a starting point for the development of our microwave-
mediated methodology, we chose the cyanation of triflate
1a as the model reaction. During the formation of 3-cyano-
3-desoxynaltrexone from the corresponding triflate under
thermal heating, Rice8 reported the best result was obtained
by using 2 equiv of Zn(CN)2 and 4% equiv of Pd(Ph3P)4 at
120 °C. We employed this condition directly to our micro-
wave-mediated reaction. The effect of varying temperatures
and time was investigated and the results are summarized
in Table 2. We found that by using 2 equiv of Zn(CN)2 and
Scheme 1
Table 2. Optimization of Microwave-Assisted Cyanation
Reaction with Aryl Triflate 1a
was converted to nitrile 2a in 60% yield. Higher temperatures
and longer reaction times did not give better yields. In the
case of triflate 1b, no or little product was obtained, even at
200 °C or with LiCl as the additive (Table 1).
Zn(CN)2
(equiv)
Pd(Ph3P)4
(equiv)
time
T
yield
(%)a
run
(min)
(°C)
1
2
3
4
5
6
7
2
2
2
2
2
1
2
4%
4%
4%
4%
4%
4%
8%
1
2
5
10
15
15
15
150
200
200
200
200
200
200
0
5
50
85
90
70
94
Table 1. Thermal Heated Cyanation Reaction with Aryl
Triflate
Zn(CN)2 Pd(Ph3P)4 time
T
yield
(%)
triflate
(equiv)
(equiv)
(h)
(°C) additive
a Yield was determined by HPLC.
1a
1a
1b
1b
1b
2
2
2
2
2
4%
4%
4%
4%
4%
10
24
24
24
12
120
150
150
200
200
-
-
-
-
60a
58a
0b
4% equiv of Pd(Ph3P)4 at 200 °C, it was possible to obtain
90% yield after 15 min of microwave irradiation (Run 5). A
decrease of Zn(CN)2 resulted in a decreased yield (Run 6),
while an increase of Pd(Ph3P)4 enhanced the yield (Run 7),
which was recognized as the best conditions in our investiga-
tion.12
<5b
LiCl
<5b
a Isolated yields. b Determined by HPLC.
Automated and focused microwave flash heating has
recently proven to be very effective in accelerating organic
transformations and has been widely applied in parallel
synthesis and in drug discovery processes. Numerous suc-
A variety of 10-ketomorphinan triflate analogues 1 with
different N-substituents were investigated under the opti-
mized reaction conditions. From the results shown in Table
3, this methodology is applicable to a wide range of N-alkyl
10-ketomorphinan triflate substrates 1 to afford products with
yields of 86-92% in 15 min. The method is extremely
efficient for the cyanation of triflate 1b, which was unsuc-
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Rouhafza, S.; Sjogren, E. B.; Smith, D. B.; Stephenson, R. A.; Talamas, F.
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1996, 39, 3503.
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2001, 57, 9225-9283. (b) Larhed, M.; Hallberg, A. Drug DiscoVery Today
2001, 6, 406-16. (c) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A.
R. J. Comb. Chem. 2002, 4, 95-105. (d) Coleman, C. M.; MacElroy, J. M.
D.; Gallagher, J. F.; O’Shea, D. F. J. Comb. Chem. 2002, 4, 87-93. (e)
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25, 3255.
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202
Org. Lett., Vol. 5, No. 2, 2003

temperature (150 °C). A longer reaction time did not improve
the yield and some other unknown products were detected
by HPLC.
Table 3. Microwave-Assisted Cyanation Reaction with Aryl
Triflate 1
From these results, it appears that the presence of a keto
group adjacent to the phenyl ring in the substrates is
important for the conversion of triflate to the corresponding
nitrile under microwave heating. This was further shown by
the cyanation of 3-methyl-4-acetylphenyl triflate 7 and
4-propionylphenyl triflate 9, which gave 91% and 87.3%
yields, respectively (Scheme 3).
Scheme 3
In conclusion, we have developed a fast and convenient
microwave-assisted, high-speed method for the displacement
of triflate by cyanide ion with Pd(Ph3P)4 as the catalyst and
Zn(CN)2 as the cyanide source. This method is highly
efficient for the preparation of 3-cyano-3-desoxy-10-keto-
morphinans 2, as well as the aryl nitriles with a keto group
adjacent to the aryl ring. The mechanism elucidating the
required presence of a keto group in the triflate and further
application of this methodology to other substrates are under
investigation.
cessful using traditional heating conditions, while a yield of
89.5% was achieved in microwave-promoted heating.
To explore the extent of this reaction, we applied this
methodology to the cyanation of triflates 3 and 5 (Scheme
2). Surprisingly, in both cases without a keto group attached
Scheme 2
Acknowledgment. We thank the National Institute on
Drug Abuse (NIDA) for financial support (DA 40595) and
Dr. Wennan Xiong for the preparation of triflate 5.
Supporting Information Available: Full experimental
details for all transformations and the analytical characteriza-
tion of all new compounds are described. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL027256P
(12) General Procedure. Microwave irradiation in a Smith Synthesizer
was used to rapidly increase the temperature to 200 °C. In a 10-mL glass
tube were placed triflate (0.2 mmol), Zn(CN)2 (47 mg, 0.4 mmol), Pd-
(Ph3P)4 (19 mg, 0.016 mmol), 5 mL of DMF, and a magnetic stir bar. The
vessel was sealed with a septum and placed into the microwave cavity.
Microwave irradiation was used and the temperature was rapidly increased
from room temperature to 200 °C. Once 200 °C was reached, the reaction
mixture was held at this temperature for 15 min and then cooled rapidly to
room temperature. The reaction vessel was opened and the contents were
poured into a separating funnel. Saturated sodium carbonate and water were
added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The
extracts were combined, washed with brine, and dried over anhydrous
sodium sulfate. After evaporation of the solvent, the residue was subjected
to silica gel column chromatography to yield the nitrile compounds.
to the B ring, poor yields were observed. In the case of triflate
3, the reaction system was very complicated under micro-
wave irradiation at 200 °C for 10 min, while at 150 °C for
15 min, the nitrile 4 was isolated in 25.5% yield with
recovery of some starting material. This also occurred with
triflate 5, where nitrile 6 was isolated in 47% yield at a lower
Org. Lett., Vol. 5, No. 2, 2003
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