N6-arylation of 2′-deoxyadenosine via copper-catalyzed direct coupling with aryl halides

Article abstract of DOI:10.1021/jo040284w

(Chemical Equation Presented) A general method for efficient N ⁶-arylation of 2′-deoxyadenosine via copper-catalyzed direct coupling with aryl iodides and bromides is described. The method is useful for aryl halides with either electron-donatin

Full text of DOI:10.1021/jo040284w

6
adducts.8-10 However, the structures of the adducts are
not established with certainty due to insufficiency of the
amounts available and the failure of attempts to develop
satisfactory methods for their synthesis.1
N -Arylation of 2′-Deoxyadenosine via
Copper-Catalyzed Direct Coupling with
Aryl Halides
1,12
Chongzhao Ran, Qing Dai, and Ronald G. Harvey*
In connection with studies aimed at devising practical
methods for synthesis of these adducts, we investigated
copper-catalyzed coupling of aryl halides with dA as a
Ben May Institute for Cancer Research, University of
Chicago, Chicago, Illinois 60637
6
13
synthetic route to N -PAH-dA adducts (Scheme 1).
rharvey@ben-may.bsd.uchicago.edu
Received November 18, 2004
6
Synthesis of N -aryl-dA adducts by Buchwald-Hartwig
Pd-catalyzed coupling of a suitably protected derivative
of dA with an o-nitroaryl bromide has been reported.
1
4a
However, the method is limited to aryl halides with
strong electron-withdrawing groups, and attempted analo-
gous coupling of aryl halides with electron-donating
groups was not successful.1 The classic copper-catalyzed
4b
1
5
Ulmann reaction of aryl halides with arylamines was
impractical because of the relatively severe conditions
required. However, it has been shown more recently that
copper-mediated coupling can take place under milder
6
A general method for efficient N -arylation of 2′-deoxyad-
15,16
conditions in the presence of various ligands.
Al-
enosine via copper-catalyzed direct coupling with aryl iodides
and bromides is described. The method is useful for aryl
halides with either electron-donating or electron-withdraw-
ing groups.
though palladium-catalyzed coupling of arylamines is
known to proceed under mild conditions,17 the choice of
copper was dictated by its lower cost, relative insensitiv-
ity to air and moisture, anticipated broader substrate
specificity, and the likelihood that protection-deprotec-
tion of the hydroxyl groups of the 2′-deoxyribose compo-
nent would be unnecessary.
Preliminary experiments were conducted to assess the
effectiveness of various ligands for the CuI-catalyzed
reaction of 4-iodotoluene with dA (Table 1). Among the
ligands most frequently employed for copper-mediated
Polycyclic aromatic hydrocarbons (PAHs) and nitro-
samines are strongly implicated as the principal cancer-
causative agents in tobacco smoke,1 and smoking of
cigarettes has been related directly to 30% of all can-
cers. PAH carcinogens formed by combustion of organic
matter, e.g., fossil fuels, are also widespread contami-
nants of urban environments.4,5
PAHs are activated by CYP enzymes to form diol
epoxide metabolites that react with the amino groups of
′-deoxyadenosine (dA) and 2′-deoxyguanosine (dG) in
2,3
(
8) Smithgall, T. E.; Harvey, R. G.; Penning, T. M. J. Biol. Chem.
1
986, 261, 6184-6191; Cancer Res. 1988, 48, 1227-1232; J. Biol.
Chem. 1988, 263, 1814-1820.
2
(9) Penning, T. M.; Onishi, S. T.; Onishi, T.; Harvey, R. G.; Chem.
Res. Toxicol. 1996, 9, 84-92. Flowers, L.; Onishi, S. T.; Penning, T.
M. Biochemistry 1997, 36, 8640. Shou, M.; Harvey, R. G.; Penning, T.
M. Carcinogenesis 1993, 14, 475-482.
DNA to form adducts that lead to mutations and tumor
4
,6,7
induction.
More recent studies have shown that the
PAH dihydrodiol precursors of the diol epoxide metabo-
lites are oxidized by aldo-keto reductase enzymes to
catechols that enter into redox cycles with O to generate
2
quinones and reactive oxygen species. The PAH quino-
nes react with DNA to form stable and depurinating
(10) A third mechanistic pathway that involves activation of PAHs
by CYP peroxidase to generate PAH radical-cations that combine with
DNA to form unstable adducts lost by depurination has also been
proposed: Cavalieri, E. L.; Rogan, E. Xenobiotica 1995, 25, 677. The
relevance of this mechanism is disputed: Melendez-Colon, V.; Luch,
A.; Seidel, A.; Baird, W. Carcinogenesis 1999, 20, 1885.
8
(11) Gopishetty, S. R.; Harvey, R. G.; Lee, S.-H.; Blair, I. A.; Penning,
T. M. In Aldo-Keto Reductases and Toxicant Metabolism; Penning, T.
M., Petrash, J. M., Eds.; ACS Symposium Series No. 865: American
Chemical Society: Washington, DC, 2003; Chapter 9, pp 127-137.
(12) McCoull, K. D.; Rindgen, D.; Blair, I. A.; Penning, T. M. Chem.
Res. Toxicol. 1999, 12, 237-246.
(13) The synthetic route to the PAH quinone adducts of 2′-deoxyri-
bonucleosides entails coupling of protected halogen-substituted deriva-
tives of the PAH quinones (or the corresponding catechols) with dA or
dG, or their derivatives, followed by deprotection (and in the case of
the catechols reoxidation back to quinones).
(14) (a) De Riccardis, F.; Bonala, R. R.; Johnson, F. J. Am. Chem.
Soc. 1999, 121, 10453-10460. (b) Lakshman, M. K.; Keeler, J. C.;
Hilmer, J. H.; Martin, J. Q. J. Am. Chem. Soc. 1999, 121, 6090-6091.
(15) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359-1470.
(16) (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. Engl. 2003,
42, 5400-5449. (b) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T.
Tetrahedron Lett. 2001, 42, 4791-4793. (c) Kelkar, A. A.; Patil, N. M.;
Chaudhari, Tetrahedron Lett. 2002, 42, 7143-7146. (d) Ma, D.; Cai,
Q.; Zhang, H. Org. Lett. 2002, 5, 2453-2455. (e) Klapars, A.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421-7428.
(17) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576,
125-146. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805-818. Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2046-2067.
*
To whom correspondence should be addressed. Fax: (773) 702-
260.
1) Review: Pfiefer, G. P.; Denissenko, M. F.; Olivier, M.; Tretya-
kova, N.; Hecht, S.; Hainaut, P. Oncogene 2002, 21, 7435-7451.
6
(
(
2) International Agency for Research on Cancer. Monographs on
the Evaluation of the Carcinogenic Risks to Humans. Tobacco Smoke
and Involuntary Smoking; IARC: Lyon, France, 2004; Vol. 83.
(3) World Health Organization. Tobacco or Health: A Global Status
Report; WHO: Geneva, 1997; pp 10-48.
4) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and
Carcinogenicity; Cambridge University Press: Cambridge, U.K., 1991.
5) International Agency for Research on Cancer. Monographs on
(
(
the Evaluation of the Carcinogenic Risk of Chemicals to Humans.
Polynuclear Aromatic Compounds, Part 1, Chemical, Environmental
and Experimental Data; IARC: Lyon, France, 1983; Vol. 32.
(
6) Jeffrey, A. M.; Weinstein, I. B.; Jennette, K.; Grzeskowiak, K.;
Nakanishi, K.; Harvey, R. G.; Autrup, H.; Harris, C. Nature (London)
977, 269, 348-350. Jennette, K.; Jeffrey, A. M.; Blobstein, S. H.;
Beland, F. A.; Harvey, R. G.; Weinstein, I. B. Biochemistry 1977, 16,
32-938.
7) Dipple, A. In DNA Adducts: Identification and Biological
1
9
(
Significance; Hemminki, K., Dipple, A., Segerb a¨ ck, D., Kadulbar, F.
F., Shuker, D., Bartsch, H., Eds.; IARC Scientific Publication No. 125;
IARC: Lyon, France, 1994; pp 107-129.
10.1021/jo040284w CCC: $30.25 © 2005 American Chemical Society
3724
J. Org. Chem. 2005, 70, 3724-3726
Published on Web 03/30/2005

SCHEME 1
TABLE 2. Coupling of Aryl Halides with
2
′-Deoxyadenosine
TABLE 1. CuI-Catalyzed Arylation of dA by
4
-Iodotoluene
6
a
ligand
time (h) N -aryl-dA yield (%)
N,N′-dimethylethylene diamine
2.5
88
81
81
68
70
1
1
,10-phenanthroline
36
,10-phenanthroline, dba
36
24
24
N-methylglycine
L-proline
a
Aryl ) 4-methylphenyl.
coupling of aryl halides with amines and amides are
1
8a
18b
19
ethylene glycols, salicylamides, amino acids, eth-
1
6e
20
ylenediamines, and 1,10-phenanthrolines. Ethylene
glycols and salicylamides have been used mainly with
alkylamines, while amino acids, ethylenediamines, and
1
,10-phenanthrolines have been used principally for
coupling arylamines. Ligands of the latter three types
were used in these preliminary experiments. Copper(I)
iodide was employed as the catalyst, and equimolar ratios
of CuI, the ligand, the reactants, and the base were used.
The yields of the adduct N -(4-methylphenyl)-2′-deoxy-
adenosine (N -aryl-dA) and the approximate times for
6
6
completion of reaction were determined (Table 1).
N,N′-Dimethylethylenediamine (DMEDA) was the most
effective ligand based on either time for completion of
reaction (2.5 h vs 24-36 h for other ligands) or adduct
yield (88%). 1,10-Phenanthroline, with or without dba,
gave a slightly lower yield of adduct (80%), but required
longer time (36 h) for completion of reaction. The ratio
of catalyst to reactants also affected the rate. With a
catalyst ratio of 100%, reaction was complete in 2-6 h.
With a ratio of 10%, 36 h were required. The effectiveness
of the bases was K
previous observations.
2
CO
3
< K
3
PO
4
2 3
) Cs CO in accord with
1
6e
A series of experiments were also conducted to compare
the reactions of various substituted aryl halides in the
CuI-catalyzed arylation of dA (Table 2). Reactions were
carried out in DMSO in the presence of DMEDA with 1
a
Yields are the average of two runs. b Reactions were carried
out in DMSO at 110 °C, with equal ratios of ArX, dA monohydrate,
c
CuI, DMEDA, and K3PO4. It was not attempted to identify the
d
components of the complex mixture of products formed. Reaction
equiv each of CuI and K
3
PO
4
at 110 °C. The reactions of
e
was incomplete after 48 h. K2CO3 was used as the base, and
the aryl iodides with dA (entries 1-10) proceeded smoothly
reaction was incomplete after 72 h. f One equivalent of NaI was
6
to provide good yields of N -aryl-dA aducts. In most cases,
added, and K3PO4 was used as the base.
minor amounts of bis-arylated adducts were also detected
as products. The electronic character of the substituents
in the aryl halide had remarkably little effect on the
facility of reaction. Thus, arylation of dA by aryl halides
with electron-donating substituents (methyl or methoxy)
(entries 1, 3, 4, and 5) took place readily. Substrates with
electron-withdrawing groups (entries 6-8) also reacted
readily with dA but required shorter time for completion
(
18) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002,
(
∼1.5 h).
4
, 581-584. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793-
As expected, steric hindrance strongly inhibited cou-
7
96;
(
19) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
pling. The hindered aryl halide 2,6-dimethyliodobenzene
entered into reaction with dA to form an adduct (entry
Soc. 1998, 120, 12459. (b) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583-
2
586. (c) Ma, D.; Cia, Q.; Zhang, H. Org. Lett. 2003, 5, 2453-2455. (d)
9
), but reaction was slow, failing to attain completion
Clement, J.-B.; Hayes, J. F.; Sheldrake, H. M.; Sheldrake, P. W.; Wells,
A. S. Synlett 2001, 1423-1427.
in 48 h. In this case, a bis-arylated adduct was not
formed.
(
20) (a) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron
Lett. 1999, 40, 2657-2660. (b) Gujadhur, R.; Bates, C. G.; Venkatara-
man, D. Org. Lett. 2001, 3, 4315-4317. (c) Goodbrand, H. B.; Hu, N.-
X. J. Org. Chem. 1999, 64, 670-674.
The aryl bromides were less reactive than the aryl
iodides, requiring longer time (3.5 h vs 2.5 h), and the
J. Org. Chem, Vol. 70, No. 9, 2005 3725

sole aryl chloride, 4-chlorotoluene (entry 14), failed to
enter into reaction. These findings accord with previous
observations on the relative reactivities of aryl halides
group. To counteract this effect, dG was converted to its
O -benzyl ether derivative, effectively converting the
6
carbonyl group into an electron-donating group. Reaction
6
(
I > Br > Cl) in copper-catalyzed arylation of aryl-
of O -benzyl-dG with 4-iodoanisole under the standard
16e
2
amines. It is also worthy of mention that 4-bromotolu-
ene (entry 12) reacted smoothly to give a good yield of
N -aryl-dA adduct (80%), despite its previous reported
failure to undergo similar reaction with a Pd catalyst.
It was also of interest to compare the relative reactivities
of two different halogen atoms in the same molecule.
Reaction of 4-chloro-1-iodobenzene with dA took place
predominantly on the iodo function to furnish up to 70%
conditions took place smoothly to afford the N -aryl-dG
adduct in good yield (79%).
6
In summary, we report a remarkably convenient
1
4b
6
method for N -arylation of 2′-deoxyadenosine. The method
entails copper-catalyzed direct coupling of unprotected
dA with aryl iodides and bromides. It is broad in scope,
allowing the use of aryl halides with either electron-
withdrawing or electron-donation groups. It also has the
practical advantage that protection-deprotection of the
OH groups of the sugar is not necessary. Although these
investigations focused primarily on arylation of dA, the
preliminary findings indicate that the method is readily
adaptable to synthesis of analogous aryl adducts of dG
and other deoxyribonucleosides. The findings also indi-
cate, on the basis of two examples (entries 15, 16), that
the method is equally applicable to the synthesis of
analogous adducts of larger polycyclic aromatic com-
pounds, presumably including the DNA adducts formed
by PAH carcinogens. Application of the method to syn-
thesis of the adducts formed by carcinogenic PAH quino-
nes, such as benzo[a]pyrene-7,8-dione, at dA and dG sites
in DNA is currently under investigation.13
6
of the expected product, N -(4-chlorophenyl)-dA. Analo-
gous reaction of 4-bromo-1-iodobenzene exhibited less
selectivity, affording a complex mixture of products.
Although methoxy groups were well tolerated (entries 3,
1
1, and 13), the presence of a free phenolic hydroxy group
(entry 10) resulted in formation of a complex mixture of
products.
Another significant finding was that the rates of
reaction of the aryl bromides were increased by addition
of sodium iodide (entries 11-13, 15, 16). Thus, reaction
2 3
of 2-bromo-6-methoxynaphthalene with dA and K CO
6
was slow in the absence of NaI, affording the N -aryl-dA
adduct in low yield (20%) after 72 h. In contrast,
analogous reaction of the same aryl halide conducted in
3 4
the presence of 1 equiv of NaI with K PO as the base
6
Experimental Section
gave the N -aryl-dA adduct in 82% yield in 3 h. This rate
enhancement is likely due to conversion of the aryl
bromide to an aryl iodide. Aryl bromides are known to
be converted to aryl iodides on treatment with CuI and
General Methods. The starting compounds, reagents, and
solvents were commercial grade and were used without further
1
13
purification. NMR ( H and C) spectra were recorded on 400
or 500 MHz spectrometers, and samples were dissolved in CD
3
-
2
1
KI or NaI. To verify this hypothesis, we carried out a
control reaction using the same reactants and conditions
in the absence of dA. Under these conditions, 2-bromo-
OD-d or DMSO-d . Chemical shifts are reported in δ ppm
4
6
relative to TMS for the proton spectra and to the deuterated
solvent for the carbon spectra. TLC was performed on silica gel
sheets containing fluorescent indicator. Chromatographic sepa-
rations were carried out on silica gel 60 M (230-400 mesh).
Melting points are uncorrected.
6
2
-methoxynaphthalene underwent smooth conversion to
-iodo-6-methoxynaphthalene, confirming that halogen
exchange is the basis of the rate enhancement effect. On
the other hand, 4-chlorotoluene failed to react with dA
in the presence of NaI and K PO , indicating that aryl
3 4
chlorides do not participate in halogen exchange under
these conditions.
Because a longer range aim of this investigation was
to develop a practical synthetic route to adducts of PAH
carcinogens with 2′-deoxyribonucleosides, these studies
were extended to include two examples of larger PAHs
6
Typical Procedure for N -Arylation of 2′-Deoxyadenos-
6
ine: Preparation of N -(4-Methylphenyl)-2′-deoxyadenos-
ine (1). 4-Iodotoluene (0.11 g, 0.5 mmol) and 2′-deoxyadenosine
monohydrate (0.14 g, 0.5 mmol) were added to a flask containing
3 4
DMSO (5.0 mL). This was followed by K PO (0.11 g, 0.5 mmol),
CuI (0.1 g, 0.5 mmol), and DMEDA (44.0 mg, 0.5 mmol). The
resulting mixture was heated to 100-110 °C and stirred for 2.5
h. The solution was cooled to rt and poured into cold water (50
mL). Then 0.5 mL of a 28-30% aqueous solution of ammonia
hydroxide was added. The product was extracted with EtOAc
(
entries 15 and 16). Copper-catalyzed coupling of 9-bro-
(3 × 30 mL), dried over Na
2
SO
4
, and purified by flash chroma-
Cl /EtOAc/CH
OH (6:6:1) to furnish the N -aryl-dA adduct (1) (0.143 g,
tography on a silica gel column eluted with CH
2
2
3
-
mophenanthrene and 1-bromopyrene with dA under the
usual conditions took place smoothly to furnish the
corresponding N -aryl-dA adducts in yields of 75% and
6
1
8
4.0%): mp 201-202 °C; H NMR (DMSO) δ 2.27 (s, 3), 2.31
m, 1), 2.75 (m, 1), 3.53 (m, 1), 3.63 (m, 1), 3.89 (dd, 1, J ) 4.0,
.0 Hz), 4.43 (m, 1), 5.13 (t, 1, J ) 6.5 Hz), 5.32 (d, 1, J ) 4.0
Hz), 6.40 (dd, 1, J ) 6.0, 6.0 Hz), 7.11 (d, 2, J ) 8.5 Hz), 7.80 (d,
6
(
7
0%, respectively.
7
The potential applicability of the copper-catalyzed
2
13
coupling method to synthesis of analogous N -aryl ad-
ducts of 2′-deoxyguanosine was also briefly examined.
However, dG failed to enter into reaction with 4-iodoani-
2, J ) 8.5 Hz), 8.35 (s, 1), 8.49 (br, 1), 9.78 (s, 1);
C NMR
(
1
DMSO) 22.4, 41.3, 63.7, 72.8, 85.8, 89.9, 122.1, 122.8, 130.7,
+
33.5, 138.8, 142.1, 150.9, 153.8, 154.0; HRMS (M + 1) calcd
3
42.1566, found 342.1575.
3 4
sole in the presence of CuI, DMEDA and K PO in DMSO
under the usual conditions employed for reaction of dA.
The most likely reason for the failure of dG to participate
in this reaction was the relatively weak nucleophilic
character of the N -amino group due to the nearby
presence of the strongly electron-withdrawing carbonyl
Acknowledgment. This investigation was sup-
ported by Grant No. P01 CA-92537 from the National
Cancer Institute, DHHS.
2
Supporting Information Available: Details of the syn-
1
13
thetic procedures and the H NMR, C NMR, and HRMS
spectra of the new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(
21) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
4844-14845. Xu, G.; Sygula, A.; Marcinow, Z.; Rabideau, P. W.
Tetrahedron Lett. 2000, 41, 9931-9934.
1
JO040284W
3726 J. Org. Chem., Vol. 70, No. 9, 2005