Synthesis of pyrrolo[2,3-d]pyrimidines via cyclocondensation of β-alkoxy- and β-amino-α-bromoaldehydes

Article abstract of DOI:10.1016/S0040-4039(00)01768-8

A series of β-alkoxy- and β-amino-α-bromoaldehydes was synthesized. The cyclocondensation of these intermediates with 2,4-diamino-6-hydroxypyrimidine yielded a series of pyrrolo[2,3-d]pyrimidines containing heteroatoms in the side chain. Choice of protecting group proved critical to the success of the bromination and cyclocondensation reactions. A number of oxygen and nitrogen protecting groups were examined and the results are described herein. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01768-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9741–9745
Synthesis of pyrrolo[2,3-d]pyrimidines via cyclocondensation
of b-alkoxy- and b-amino-a-bromoaldehydes
Charles J. Barnett and Lana M. Grubb*,†
Chemical Process Research and Development, Lilly Research Laboratories, a division of Eli Lilly and Company,
Indianapolis, IN 46285-4813, USA
Received 21 August 2000; revised 2 October 2000; accepted 3 October 2000
Abstract
A series of b-alkoxy- and b-amino-a-bromoaldehydes was synthesized. The cyclocondensation of these
intermediates with 2,4-diamino-6-hydroxypyrimidine yielded a series of pyrrolo[2,3-d]pyrimidines contain-
ing heteroatoms in the side chain. Choice of protecting group proved critical to the success of the
bromination and cyclocondensation reactions. A number of oxygen and nitrogen protecting groups were
examined and the results are described herein. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: pyrrolo[2,3-d]pyrimidines; a-bromoaldehydes; cyclocondensation.
The pyrrolo[2,3-d]pyrimidine ring system is a common motif in several natural products and
biologically active molecules, including Q base (1), Nucleoside Q (2), and cadeguomycin (3).1
Multitargeted antifolate LY231514 (4), of particular interest as a potential pharmaceutical, also
features the pyrrolo[2,3-d]pyrimidine ring system.
OH
O
O
O
H
N
COOH
O
N
H
HN
H2N
HN
H2N
O
N
R
N
HO
N
R
N
OH
O
N
OH
3
1 Q base (R = H)
2 Nucleoside Q (R = ribose)
Cadeguomycin
R = ribose
4
HN
H2N
LY231514
N
H
* Corresponding author. Present address: Albany Molecular Research, Inc., 21 Corporate Circle, PO Box 15098,
Albany, NY 12212-5098, USA. Tel: 518-464-0279; e-mail: lanag@albmolecular.com
† Lilly Postdoctoral Fellow 1999–2000.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01768-8

9742
We recently published a practical synthesis of 4 in which the key step was the cyclocondensa-
tion of 2,4-diamino-6-hydroxypyrimidine (5) with bromoaldehyde 6 (Scheme 1) to give
pyrrolopyrimidine 7.2 In the case of 7, an all carbon chain links the pyrrolopyrimidine to the
pendant aryl group. While condensations of this sort have been reported previously in the
literature,3 to our knowledge condensations of b-alkoxy- and b-amino-a-bromoaldehydes to
form pyrrolopyrimidines containing heteroatoms in the functionality found at the 5-position in
natural products 1, 2, and 3 have not previously been reported. We sought to expand the scope
of this cyclization to include syntheses of molecules containing heteroatom linkers, envisioning
that such a strategy would provide a new entry into this class of compounds. Determination of
oxygen and nitrogen protecting groups that would allow for the synthesis of the b-amino- and
b-alkoxy-a-bromoaldehydes needed for the cyclization reaction was necessary to achieve this
goal. Stability of these bromoaldehyde intermediates once obtained also proved important to the
success of the cyclization reaction. Here we report our results thus far.
CO2Me
CO2Me
CH3CN/H2O
O
O
N
Br
HN
H2N
HN
H2N
+
NaOAc
N
H
N
NH2
O
5
6
7
Scheme 1.
In the b-alkoxy protected series, two protecting groups examined, benzyl and TBDPS, proved
effective. b-Alkoxybromoaldehydes 9a and 9b were synthesized in two steps in 90–95% overall
yield from monoprotected 1,3-propanediols 8a and 8b (Scheme 2).4 Oxidation of the alcohols5
proceeded smoothly, followed by treatment with dibromobarbituric acid (DBBA) in acetonitrile6
to give bromoaldehydes 9a or 9b in 90–95% overall yield.
a-b
RO
O
RO
OH
90-95%
Br
9a R = Bn
9b R = TBDPS
8a R = Bn
8b R = TBDPS
Scheme 2. Reagents: (a) TEMPO, KBr, NaOCl, H2O/CH2Cl2; (b) DBBA, CH3CN
Several other oxygen protecting groups examined were not effective. Oxidation of mono-
TBDMS, -TIPS, -benzoyl, and -trityl protected 1,3-propanediols, for example, proceeded
smoothly but attempts to brominate the resulting aldehydes led only to decomposition of
1
starting material with no significant amount of bromoaldehyde formation as determined by H
NMR.
We next turned our attention to the protected b-aminoaldehyde series. Bromoaldehyde 11 was
synthesized in three steps from potassium phthalimide 10 (Scheme 3). Alkylation of 10 with
3-bromopropionaldehyde dimethyl acetal was followed by treatment with acid, which gave the
known aldehyde 11.7 Bromination with DBBA in CH3CN gave bromoaldehyde 12 in 60–65%
overall unoptimized yield.

9743
O
N
O
O
N
O
O
c
a,b
O
NK
O
O
Br
85-90%
70-75%
10
11
12
Scheme 3. Reagents: (a) 3-bromopropionaldehyde dimethyl acetal, DMF; (b) THF, HCl; (c) DBBA, CH3CN
A series of nitrogen protected cyclopentylamines was synthesized as a model for the synthesis
of Q Base (1) (Scheme 4). Several protecting group strategies were examined in order to
determine which might permit high yielding bromination of aldehydes. Tosyl and o-nosyl groups
gave the best results. Cyclopentylamine derivatives 15a and 15b were synthesized in five steps,
beginning with reductive amination8 of cyclopentylamine (13) and an appropriately functional-
ized three carbon aldehyde. Installation of the protecting group on nitrogen (Ts or Ns) provided
intermediates 14a and 14b in 75–85% yield. Further elaboration of 14a and 14b was accom-
plished by removal of the oxygen protecting group, oxidation to the aldehyde, and bromination
using DBBA to give bromoaldehydes 15a and 15b in 75–85% yield.
NH2
R'N
OR
c-e
R'N
O
a, b
Br
75-85%
75-80%
14a R = Bn, R' = Ts
14b R = TBDPS, R' = o-Nosyl
13
15a R' = Ts
15b R' = o-Nosyl
Scheme 4. Reagents: (a) ROCH2CH2CHO, MeOH, NaBH4; (b) R%Cl, Et3N, CH2Cl2; (c) remove R; (d) TEMPO, KBr,
NaOCl, H2O/CH2Cl2; (e) DBBA, CH3CN
Use of a sulfonamide protecting group on nitrogen was essential for successful bromination
of the aldehyde.9 Other nitrogen protecting groups examined included the BOC, acetyl, and
benzoyl groups. b-Aminoalcohols containing these protecting groups could be cleanly oxidized
to the corresponding aldehydes. However, upon treatment of the aldehyde with DBBA only
decomposition of the starting aldehyde was observed. In each case no appreciable amount of the
1
desired b-amino-a-bromoaldehydes was observed by H NMR.
With the determination of most suitable protecting groups and synthesis of a series of
bromoaldehydes achieved, the cyclocondensation of these substrates was examined (Table 1).
We were gratified to achieve in moderate to good yields the synthesis of a series of pyrrolo[2,3-
d]pyrimidines 16 via cyclocondensation of these bromoaldehyde substrates (9a–b, 12, 15a–b).
Conditions examined were the same as those reported in the synthesis of 4.2 A mixture of
bromoaldehyde, 2,4-diamino-6-hydroxypyrimidine, and NaOAc were warmed in MeCN/H2O
for 2–3 h, after which the precipitated product was filtered.10 Yields shown in Table 1 represent
isolated yields and are unoptimized. The generality of this reaction has thus been greatly
enhanced from that previously reported.
In conclusion, we have successfully synthesized a series of pyrrolo[2,3-d]pyrimidines from
b-amino- and b-alkoxy-a-bromoaldehydes. The key condensation step as well as the bromina-
tion of the aldehydes was sensitive to the protecting group employed. Utility of this new
methodology is currently being demonstrated by the total synthesis of Q Base (1). Details of this
work will be reported elsewhere.

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Table 1
CH3CN/H2O
NaOAc
O
O
N
X
X
HN
H2N
Br
O
HN
H2N
+
N
H
N
NH2
5
16
a-Bromoaldehyde
Product
Yield (%)
9a, X=OBn
9b, X=OTBDPS
12, X=N-phth
15a, X=N(cyclopentyl)Ts
15b, X=N(cyclopentyl)Ns
16a
16b
16c
16d
16e
80
50
75
45
68
Acknowledgements
The authors would like to thank Michael E. Kobierski for valuable discussions and sugges-
tions concerning the cyclocondensation reactions.
References
1. Some selected references: Kondo, T.; Oghi, T.; Goto, T. Chem. Lett. 1983, 419–422. Kondo, T.; Okamoto, K.;
Oghi, T.; Goto, T. Tetrahedron 1986, 42, 207–213. Kondo, T.; Okamoto, K.; Yamamoto, M.; Goto, T.
Tetrahedron 1986, 42, 199–206. Ramasamy, K.; Joshi, R. V.; Robins, R.; Revankar, G. R. J. Chem. Soc., Perkin
Trans. 1 1989, 2375–2384.
2. Barnett, C. J.; Wilson, T, M.; Kobierski, M. E. Org. Process Res. Dev. 1999, 3, 184–188. Alimta™, the disodium
salt of 1, is currently in Phase III clinical trials for treatment of mesothelioma.
3. (a) Secrist, J. A.; Liu, P. S. J. Org. Chem. 1978, 43, 3937–3941. (b) Noell, C. W.; Robins, R. K. J. Heterocyclic
Chem. 1964, 1, 34–41.
1
4. All new compounds were characterized by H and 13C NMR, IR and HRMS where possible. Bromoaldehydes,
1
however, were unstable and used as obtained from the bromination reactions after analysis by H NMR.
5. Anelli, P. L.; Montanari, F.; Quici, S. Org. Synth. 1990, 69, 212–219.
6. Grundke, G.; Keese, K.; Rimpler, M. Chem. Ber. 1985, 118, 4288–4291.
7. Baxter, A. D.; Montana, J.; Owen, D. A. PCT Int. Appl. 9635714, 1996; Chem. Abstr. 1997, 126, 60363.
8. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
3849–3862.
9. Triflyl and trifluoroacetyl protected b-aminoaldehydes also gave the desired a-bromoaldehydes. However,
cyclization reactions performed with these substrates gave only trace amounts of the desired pyrrolopyrimidine.
The reason for this result is not immediately clear but could be related to the stability of the b-amino-a-bromo-
aldehydes under the cyclization conditions, with decomposition of the bromide occurring before significant
product formation was achieved.
10. A representative procedure is as follows: Bromide 9a (22.7 mmol), 2,4-diamino-6-hydroxyprimidine (22.8 mmol),
and sodium acetate (47.1 mmol) were combined in 100 mL of 1:1 acetonitrile/water. The mixture was warmed to
40°C, dissolving all solids within 5–10 min. After heating for 1–2 h the product (16a) precipitated from the
reaction mixture. After continued stirring for 1–2 h to ensure complete reaction, the mixture was cooled to room
temperature and the product isolated by filtration. The filtrate was concentrated to approximately one-half
volume and filtration yielded a second batch of product for a total of 5.50 g (20.3 mmol) 16a. Spectroscopic data

9745
1
for 16a: H NMR (DMSO-d6) l 4.51(s, 2 H), 4.57 (s, 2 H), 6.07 (s, 2 H), 6.60 (s, 1 H), 7.23–7.33 (m, 5 H), 10.29
(s, 1 H), 10.90 (s, 1 H). 13C NMR (DMSO-d6) l 64.6, 70.9, 98.5, 115.0, 115.7, 127.1, 127.4, 128.0, 138.9, 151.2,
152.3, 159.0. IR (cm−1) (KBr) 3324, 3158, 2860, 1632, 1350. HRMS calculated for C14H14N4O2+Na 293.1014,
found 293.1013. In the case of 16b separation of the reaction solution into two phases was observed but little
solid precipitated. Isolation of the product was accomplished by repeated extraction of the reaction mixture with
CH2Cl2 or CHCl3, drying with MgSO4, and concentration to give the product as a pink solid.
.