Synthesis of Pyrrolo[2,3-d]pyrimidines by Copper-Mediated Carbomagnesiations of N-Sulfonyl Ynamides and Application to the Preparation of Rigidin A and a 7-Azaserotonin Derivative

Article abstract of DOI:10.1002/chem.201602519

The treatment of readily available N-alkynyl-5-iodo-6-sulfamido-pyrimidines with iPrMgCl?LiCl followed by a transmetalation with CuCN?2 LiCl produces, after intramolecular carbocupration, metalated pyrrolo[2,3-d]pyrimidines. Quenching of these pyrimidines with allylic halides or acid chlorides results in polyfunctional pyrrolo[2,3-d]pyrimidines. Further reaction with ICl and a Negishi cross-coupling, using PEPPSI-iPr as the catalyst, furnishes fully substituted N-heterocycles. A formal synthesis of the marine alkaloid rigidin A has been achieved as well as the preparation of a derivative of 7-azaserotonine, related to the natural hormone serotonin.

Full text of DOI:10.1002/chem.201602519

DOI: 10.1002/chem.201602519
Full Paper
&
Synthetic Methods
Synthesis of Pyrrolo[2,3-d]pyrimidines by Copper-Mediated
Carbomagnesiations of N-Sulfonyl Ynamides and Application to
the Preparation of Rigidin A and a 7-Azaserotonin Derivative
Johannes Nickel, Maitane Fernꢀndez, Lydia Klier, and Paul Knochel*[a]
Abstract: The treatment of readily available N-alkynyl-5-
iodo-6-sulfamido-pyrimidines with iPrMgCl·LiCl followed by
a transmetalation with CuCN·2LiCl produces, after intramo-
lecular carbocupration, metalated pyrrolo[2,3-d]pyrimidines.
Quenching of these pyrimidines with allylic halides or acid
chlorides results in polyfunctional pyrrolo[2,3-d]pyrimidines.
Further reaction with ICl and a Negishi cross-coupling, using
PEPPSI-iPr as the catalyst, furnishes fully substituted N-het-
erocycles. A formal synthesis of the marine alkaloid rigidin A
has been achieved as well as the preparation of a derivative
of 7-azaserotonine, related to the natural hormone seroto-
nin.
Introduction
The preparation of condensed N-heterocyclic molecules is of
great importance due to their biological properties.[1,2] Whereas
the preparation of indoles is well established, the synthesis of
highly substituted azaindoles is still a synthetic challenge. Re-
cently, we and others developed a new preparation of func-
tionalized indoles[3] and azaindoles[4] of type 1 from bromo N-
sulfonyl ynamides[7] of type 2 (Scheme 1) using an intramolecu-
lar carbocupration[5] triggered by a Br–Mg exchange performed
with iPrMgCl·LiCl.[6] The resulting organomagnesium reagent 3
undergoes a room temperature cyclization in the presence of
CuCN·2LiCl[8] leading to cuprated intermediates of type 4,
which, after quenching with various electrophiles, afford func-
tionalized N-heterocycles of type 1. Since azaindoles and pyrro-
lo[2,3-d]pyrimidines are common N-heterocycles found in natu-
ral products and in drug candidates, we have further investi-
gated the preparation of relevant natural products and deriva-
tives such as the marine alkaloid rigidin A[9] (5) as well as a de-
rivative of 7-azaserotonin[10] (6), related to the natural hormone
serotonin (7)[11] (Scheme 2).
Scheme 1. Copper-mediated carbomagnesation of ynamides of type 2 lead-
ing to indoles and azaindoles of type 1.
Scheme 2. Natural products rigidin A, 7-azaserotonin, and serotonin.
overall yield (Scheme 3). Copper-catalyzed amination[14] with p-
toluenesulfonamide in the presence of Cs2CO3 in MeCN provid-
ed pyrimidyl N-sulfonylamide (10) in 68% yield. After metala-
tion with KHMDS (HMDS=phexamethyldisilazane), treatment
with phenyl((trimethylsilyl)ethynyl)iodonium triflate[15] afforded
6-substituted pyrimidyl N-sulfonyl ynamide (11).
Compound 11 was then submitted to an I–Mg exchange
using iPrMgCl·LiCl (THF, À408C, 2 h). After full conversion,[16]
the intermediate magnesium reagent of type 3 underwent
transmetalation to the corresponding copper species using
CuCN·2LiCl. A smooth trans-carbocupration proceeded at 258C
within 16 h leading to heterocyclic intermediate of type 4.
After hydrolysis, the pyrrolo[2,3-d]pyrimidine (12a) was ob-
tained in 67% isolated yield (Table 1, entry 1). Allylation of the
Results and Discussion
As a model system for the preparation of rigidin A, we first pre-
pared an N-sulfonyl ynamide derived from 2,4-dimethoxypyri-
midine (8) with a double magnesiation/iodolysis sequence[12]
using TMPMgCl·LiCl[13] (TMP=2,2,6,6-tetramethylpiperidyl) and
iodine to afford 5,6-diiodo-dimethoxypyrimidine (9) in 65%
[a] J. Nickel, Dr. M. Fernꢀndez, Dr. L. Klier, Prof. Dr. P. Knochel
Ludwig Maximilians-Universitꢁt Mꢂnchen
Department Chemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢂnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article can be found under
http://dx.doi.org/10.1002/chem.201602519.
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We further demonstrated that the 3-TMS-substituted pyrro-
lo[2,3-d]pyrimidine (12b) can be readily converted into the cor-
responding iodide (13) by using ICl[17] in CH2Cl2 (08C, 10 min)
in 74% yield. Negishi cross-coupling[18] with various zinc re-
agents[19] using PEPPSI-IPr[20] furnished the arylated products
(14a–c) in 52–63% yield (Scheme 4).
Scheme 3. Preparation of the N-sulfonyl ynamide (11).
copper intermediate of type 4 with allyl bromide or 2-cyclo-
hexenyl bromide provided the allylated products (12b–c) in
57–81% yield (entries 2–3). Finally acylation with various aro-
matic acid chlorides furnished the substituted benzoylated N-
heterocycles (12d–g) in 53–77% yield (entries 4–7).
Scheme 4. Transformation of the TMS-substituted pyrrolo[2,3-d]pyrimidine
12b to the 3-iodocompound 13 followed by Negishi cross-couplings.
With these results in hand, we applied this method to the
synthesis of marine natural product rigidin A (5; Scheme 5).
Thus, the iodolysis of 12e with ICl provided the 3-iodo-deriva-
tive (15) in 89% yield. Desulfonylation with KOH in a mixture
of MeOH:THF led to the pyrrolo[2,3-d]pyrimidine (16) in 61%
yield. The N-heterocycle 16 was further converted to rigidin A
(5), according to the procedure of Sakamoto,[21] in two steps. A
Suzuki reaction[22] afforded the fully substituted heterocycle 17
(57% yield), followed by a deprotection of the four methoxy-
substituents leading to rigidin A (5) in five steps starting from
the N-sulfonyl ynamide (11) in about 8% overall yield.
Table 1. Functionalized pyrrolo[2,3-d]pyrimidines of type 12 obtained by
copper-mediated carbomagnesiation of ynamide 11 and subsequent re-
action with various electrophiles (EÀX).
Entry
1
Electrophile
H2O
Product
Yield [%][a]
67
Finally, we performed a short synthesis of a derivative of 7-
azaserotonine (18) starting from commercially available 2-
amino-3,5-dibromopyridine (19) (Scheme 6). First, the phenyl-
sulfonylation of the pyridine 19 with PhSO2Cl followed by its
conversion to the corresponding ynamide 20 using KHMDS
and phenyl((trimethylsilyl)ethynyl)iodonium triflate proceeded
in about 68% overall yield. Regioselective Br–Mg exchange
2
3
81
57
4
67
5
6
7
71
77
53
[a] Isolated yield of analytically pure products.
Scheme 5. Synthesis of rigidin A (5).
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with iPrMgCl·LiCl followed by a transmetalation with CuCN·2
LiCl provided, after an intramolecular carbocupration (258C,
16 h), the azaindole 21 in 89% yield. A second Br–Mg ex-
change followed by a borylation with methoxyboronic acid pi-
nacol ester[23] and subsequent oxidation (30% H2O2, NaOH,
258C, 15 h) provided the 5-hydroxyazaindole 22 in 73% yield.
Protection of the free phenolic hydroxyl group with pivaloyl
chloride and iodination with ICl furnished the 3-iodoazaindole
23 in 83% yield. I–Mg exchange of 23 with MeMgCl and trans-
metalation with CuCN·2LiCl, followed by an opening[24] of N-
tosyl aziridine (258C, 5 h) gave the N-sulfonyl azaserotine deriv-
ative 18 in 72% yield.[25] The overall yield of the 7-azaseroto-
nine derivative 18 was approximately 26% for 7 steps begin-
ning with the aminopyridine (19).
Acknowledgements
This research has received funding from the Deutsche For-
schungsgesellschaft (SFB 749). We also thank BASF AG (Lud-
wigshafen) and Rockwood Lithium GmbH (Frankfurt) for the
generous gifts of chemicals.
Keywords: azaserotonin · carbomagnesation · cyclisation · N-
heterocycles · rigidin A
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In summary, we have reported a room temperature, intramo-
lecular copper-mediated carbomagnesiation procedure for the
synthesis of functionalized pyrrolo[2,3-d]pyrimidines of type 12
and 7-azaindole derivatives. Further functionalization of these
N-heterocycles gave access to the marine alkaloid rigidin A and
a derivative of 7-azaserotonin.
Experimental Section
Typical procedure for intramolecular copper-mediated carbo-
magnesations: To a solution of ynamide 11 (1.0 equiv) in THF
(0.5m) iPrMgCl·LiCl (1.22m in THF, 1.1 equiv) was added dropwise
at À408C and stirred at this temperature for 2 h. After addition of
THF (0.05m), CuCN·2LiCl (1.0m in THF, 1.1 equiv) was added and
the solution was stirred at 258C for 24 h. The reaction mixture was
then cooled to À308C, quenched with an electrophile (1.2 equiv),
and slowly allowed to warm to 258C. After addition of aqueous
NH4Cl:NH3 solution (19:1), the reaction mixture was extracted with
EtOAc, the organic layers were dried (MgSO4), and concentrated in
vacuo. The crude residue was purified by flash column chromatog-
raphy on silica gel to yield the corresponding products of type 12.
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Received: May 27, 2016
Published online on && &&, 0000
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FULL PAPER
&
Synthetic Methods
J. Nickel, M. Fernꢀndez, L. Klier,
P. Knochel*
&& – &&
Synthesis of Pyrrolo[2,3-d]pyrimidines
by Copper-Mediated
Carbomagnesiations of N-Sulfonyl
Ynamides and Application to the
Preparation of Rigidin A and a 7-
Azaserotonin Derivative
On the route to biomolecules: A mild
and general intramolecular copper-
mediated carbomagnesiation procedure
was developed for the synthesis of func-
tionalized N-heterocycles starting from
readily available ynamides. Subsequent
reactions offer short synthetic routes to
biologically relevant molecules such as
rigidin A or a derivative of 7-azaseroto-
nin.
Chem. Eur. J. 2016, 22, 1 – 5
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